First-line Treatment Of Metastatic Colorectal Cancer Research Articles

Mismatch Repair-Deficient Colorectal Cancer: Building on Checkpoint Blockade.

Colorectal cancer (CRC) with deficient DNA mismatch repair (dMMR) is characterized by hypermutation leading to abundant neoantigens that activate an antitumor immune response in the tumor microenvironment. Immune checkpoint inhibitors (ICIs) have transformed the treatment of this subset of CRC and other solid tumors with dMMR, by producing frequent and durable responses that extend patient survival. Recently, the anti-programmed death-1 (PD-1) antibody pembrolizumab was shown to produce significantly longer progression-free survival with fewer adverse events compared with chemotherapy as first-line treatment of metastatic CRC (mCRC) with dMMR. Accordingly, single-agent pembrolizumab represents a new standard of care for dMMR mCRCs including patients with Lynch syndrome and the more common sporadic cases. Furthermore, data indicate that the combination of PD-1 and cytotoxic T-cell lymphocyte-4 inhibitors was more effective than single-agent PD-1 inhibition in patients with dMMR mCRCs, suggesting nonredundant mechanisms of action. Although the benefit of ICIs is currently limited to metastatic disease, studies evaluating ICIs as neoadjuvant and adjuvant therapy in earlier-stage dMMR CRC are ongoing. Despite success of ICIs in the treatment of metastatic dMMR cancers, an appreciable proportion of these tumors demonstrate intrinsic or acquired resistance, and biomarkers to identify these patients are needed. Advances in the understanding of immunotherapy resistance mechanisms hold promise for both biomarker identification and development of novel strategies to circumvent treatment resistance. In this review, we present a comprehensive overview of the evidence for the role of immunotherapy in the treatment of dMMR CRC, discuss resistance mechanisms, and outline potential strategies to circumvent primary and secondary resistance with the goal of broadening the benefit of ICIs.

A Possible Distinct Molecular Subtype (Quintuple-Wildtype) of Metastatic Colorectal Cancer in First-Line Anti-EGFR Therapy with Cetuximab Plus FOLFIRI – Palliative Precision Therapy and a Multidisciplinary Treatment Approach: Interim Analysis of the IVOPAK II Trial with Early Results

Objective: The study aimed to prospectively evaluate a new molecular biomarker panel (KRAS, NRAS, BRAF, PIK3CA, and ERBB2) for palliative first-line treatment of colorectal cancer (CRC), including a multidisciplinary treatment approach. The rate of secondary metastasis resections was assessed. Patients and Methods: A total of 40 patients with definitively nonresectable metastatic CRC were enrolled from 10 centers before the interim analysis (June 2019) of the IVOPAK II trial (Interdisciplinary Care with Quality Control in Palliative Treatment of Colorectal Cancer). After determination of 5 molecular biomarkers in the tumor (KRAS, exons 2–4; NRAS, exons 2–4; BRAF V600E; PIK3CA; and ERBB2), patients in the IVOPAK II study received FOLFIRI plus cetuximab for all-RAS/quintuple-wildtype disease and FOLFIRI plus bevacizumab in the case of RAS mutations. The current article presents the early description of the clinical outcome of the interim analysis of IVOPAK II comparing the all-RAS/quintuple-wildtype and RAS-mutations populations, including a multidisciplinary-treated case report of a quintuple-wildtype patient. Results: The quintuple-wildtype population treated with FOLFIRI plus cetuximab in first-line exhibited a significantly higher response rate and enhanced early tumor shrinkage in the interim analysis than the RAS-mutations population, as well as a high rate of secondary metastatic resections. Conclusion: Initial results of this new biomarker panel (quintuple-wildtype) are promising for anti-EGFR therapy with cetuximab plus doublet chemotherapy (FOLFIRI) in first-line treatment of metastatic CRC. These results warrant confirmation with higher case numbers in the IVOPAK II trial.

A randomized phase II study comparing oral S-1 plus 24-hour infusion of irinotecan (Iri) and bevacizumab (Bev) with FOLFIRI plus bevacizumab in patients with metastatic colorectal cancer (MCRC).

613 Background: FOLFOX or FOLFIRI plus Bev is a first-line treatment for MCRC. Recent studies have confirmed that oral S-1 combined with Iri and Bev is equivalent to FOLFIRI plus Bev. Iri is usually administered as a short-term 90-min. infusion. However, the cytocidal activity is S-phase specific, and carboxylesterases, that convert Iri into SN-38, are less likely to become saturated when Iri is given as a long-term infusion. Therefore, a low dose of Iri given as a long-term infusion is expected to enhance antitumor activity. We conducted a randomized phase II study to compare this regimen with FOLFIRI plus Bev. Methods: The subjects comprised 120 chemotherapy-naïve patients with MCRC. The study group received 24-hr infusion of Iri at a dose of 125 mg/m2 on days 1 and 15, combined with oral S-1 80 mg/m2 on days 1 to 14. The FOLFIRI group received Iri at a dose of 150 mg/m2, 5-FU given at a dose of 400 mg/m2 as a bolus injection and at a dose of 2400 mg/m2 as a 46 hr-infusion, 200 mg/m2 of leucovorin on days 1 and 15. Bev was given at a dose of 5.0 mg/kg on days 1 and 15 in both groups. Treatment was repeated every 4 weeks. The primary endpoint was the 1 y progression-free survival (PFS). Secondary endpoints were PFS, response rates (RR), overall survival (OS), and adverse events (AEs). Results: From October 2013 through December 2017, a total of 61 patients assigned to receive IRIS plus Bev (the A group) and 59 patients assigned to receive FOLFIRI plus Bev (the B group) were included in the analysis. The 1y RFS was 37.3% in the A group and 17.0% in the B group (p = 0.0281). The PFS was 10.2 mon in the A group and 10.0 mon in the B group, and the median OS was 27.0 mon and 28.6 mon, respectively (p = 0.26, p = 0.68). RR was significantly higher in the A group (87.0%) than in the B group (61.7%) (p = 0.005). The main grade 3 or 4 AEs were neutropenia (27.8%) and diarrhea (11.1%) in the A group and neutropenia (23.4%) and leukopenia (6.4%) in the B group. Conclusions: Our results showed that Iri, given biweekly as a 24-hour infusion in combination with oral S-1 and Bev, is a highly effective and well-tolerated regimen for the first-line treatment of MCRC. Clinical trial information: UMIN000014664.

Protocol for Combined Analysis of FOXFIRE, SIRFLOX, and FOXFIRE-Global Randomized Phase III Trials of Chemotherapy +/- Selective Internal Radiation Therapy as First-Line Treatment for Patients With Metastatic Colorectal Cancer

BackgroundIn colorectal cancer (CRC), unresectable liver metastases are associated with a poor prognosis. The FOXFIRE (an open-label randomized phase III trial of 5-fluorouracil, oxaliplatin, and folinic acid +/- interventional radioembolization as first-line treatment for patients with unresectable liver-only or liver-predominant metastatic colorectal cancer), SIRFLOX (randomized comparative study of FOLFOX6m plus SIR-Spheres microspheres versus FOLFOX6m alone as first-line treatment in patients with nonresectable liver metastases from primary colorectal carcinoma), and FOXFIRE-Global (assessment of overall survival of FOLFOX6m plus SIR-Spheres microspheres versus FOLFOX6m alone as first-line treatment in patients with nonresectable liver metastases from primary colorectal carcinoma in a randomized clinical study) clinical trials were designed to evaluate the efficacy and safety of combining first-line chemotherapy with selective internal radiation therapy (SIRT) using yttrium-90 resin microspheres, also called transarterial radioembolization.ObjectiveThe aim of this analysis is to prospectively combine clinical data from 3 trials to allow adequate power to evaluate the impact of chemotherapy with SIRT on overall survival.MethodsEligible patients are adults with histologically confirmed CRC and unequivocal evidence of liver metastases which are not treatable by surgical resection or local ablation with curative intent at the time of study entry. Patients may also have limited extrahepatic metastases. Final analysis will take place when all participants have been followed up for a minimum of 2 years.ResultsEfficacy and safety estimates derived using individual participant data (IPD) from SIRFLOX, FOXFIRE, and FOXFIRE-Global will be pooled using 2-stage prospective meta-analysis. Secondary outcome measures include progression-free survival (PFS), liver-specific PFS, health-related quality of life, response rate, resection rate, and adverse event profile. The large study population will facilitate comparisons of low frequency adverse events and allow for more robust safety analyses. The potential treatment benefit in those patients who present with disease confined to the liver will be investigated using 1-stage IPD meta-analysis. Efficacy will be analyzed on an intention-to-treat basis.ConclusionsThis analysis will assess the impact of SIRT combined with chemotherapy on overall survival in the first-line treatment of metastatic CRC. If positive, the results will change the standard of care for this disease.Trial RegistrationFOXFIRE ISRCTN Registry ISRCTN83867919; http://www.isrctn.com/ISRCTN83867919 (Archived by WebCite at http://www.webcitation.org/6oN7axrvA). SIRFLOX ClinicalTrials.gov NCT00724503; https://clinicaltrials.gov/ ct2/show/NCT00724503 (Archived by WebCite at http://www.webcitation.org/6oN7lEGbD). FOXFIRE-Global ClinicalTrials.gov NCT01721954; https://clinicaltrials.gov/ct2/show/NCT01721954 (Archived by WebCite at http://www.webcitation.org/ 6oN7vvQvG).

Regorafenib plus modified FOLFOX6 as first-line treatment of metastatic colorectal cancer: A phase II trial

BackgroundThe oral multikinase inhibitor regorafenib improves overall survival (OS) in patients with metastatic colorectal cancer (CRC) for which all standard treatments have failed. This study investigated regorafenib plus modified FOLFOX (mFOLFOX6) as first-line treatment of metastatic CRC. MethodsIn this single-arm, open-label, multicentre, phase II study, patients received mFOLFOX6 on days 1 and 15, and regorafenib 160mg orally once daily on days 4–10 and 18–24 of each 28-day cycle. The primary end-point was centrally assessed objective response rate (ORR). Secondary end-points included disease control rate (DCR), OS, progression-free survival (PFS) and safety. ResultsMedian overall treatment duration with any study drug was 9.9months (range 0.6–19.6); median treatment duration with regorafenib was 7.7months (range 0.1–19.5); six patients remained on regorafenib for more than 1year. Fifty-three patients received at least one dose of regorafenib. ORR was 43.9% (all partial responses); DCR was 85.4%; median OS was not reached; median PFS was 8.5months. Treatment-emergent adverse events were experienced by all patients but were manageable with dose modifications. ConclusionRegorafenib+mFOLFOX6 as first-line treatment in patients with metastatic CRC did not improve ORR over historical controls. Regorafenib plus mFOLFOX6 did not appear to be associated with a markedly worse tolerability profile versus mFOLFOX6 alone.ClinicalTrials.gov identifier: NCT01289821.

Comparison between three oxaliplatin-based regimens with bevacizumab in patients with metastatic colorectal cancer.

BackgroundA previous pivotal Phase III study (NO16966) demonstrated the benefit of the addition of bevacizumab (BV) to oxaliplatin-based regimens in metastatic colorectal cancer (MCRC). Our study evaluated the safety and efficacy of three oxaliplatin-based chemotherapy regimens (FOLFOX4 [intravenous twice-bolus and twice-infusional 5-fluorouracil/folinic acid plus oxaliplatin], mFOLFOX6 [intravenous once-bolus and once-infusional 5-fluorouracil/folinic acid plus oxaliplatin], and XELOX [capecitabine plus oxaliplatin]) plus BV in the first-line treatment of MCRC patients.MethodsPatients with MCRC who started treatment between June 2007 and September 2010 were evaluated in this retrospective cohort study. We also evaluated early objective tumor response (EOTR) within 12 weeks, which was defined as a relative change of ≥30% in the sum of the longest diameters of target lesions when compared with baseline. The primary study endpoints were progression-free survival (PFS) and response rate.ResultsA total of 185 patients received the following chemotherapy: FOLFOX4 + BV (FF4 arm, n=85), mFOLFOX6 + BV (FF6 arm, n=40), and XELOX + BV (XELOX arm, n=60). The overall response rates were 61.2%, 72.5%, and 75.0% (95% confidence interval: 50.6%–71.8%, 58.0%–87.0%, and 63.7%–86.3%). Median PFS was 18.0, 15.5, and 13.7 months, respectively (log-rank: P=0.254; data cut-off: May 2013). Patients with EOTR (n=117) had significantly better PFS than those without-EOTR (n=68) (17.5 versus 12.7 months, P=0.004).ConclusionThis study suggests that these three BV plus oxaliplatin-based treatments might have comparable benefit in terms of tumor response and PFS. Moreover, EOTR may be a predictive factor for PFS in patients with MCRC.

Cost-effectiveness of first-line treatments for patients with KRAS wild-type metastatic colorectal cancer.

Combinations of chemotherapy regimens and monoclonal antibodies have been demonstrated to improve clinical outcomes in patients with metastatic colorectal cancer (mcrc). Although these combination treatment strategies are safe and effective in first-line treatment for mcrc, little is known about their economic consequences and resource allocation implications. In the present study, we evaluated the cost-effectiveness of bevacizumab plus folfiri, cetuximab plus folfiri, and panitumumab plus folfiri for patients with KRAS wild-type mcrc. A Markov model simulated the lifetime patient outcomes and costs of each first-line treatment strategy and subsequent lines of treatment from the perspective of the health care payer in Ontario. The model was parameterized using data from the Ontario Cancer Registry, Ontario health administrative databases, and published randomized control trials. Patient outcomes were measured in quality-adjusted life years (qalys), and costs were measured in monetary terms. Costs and outcomes were both discounted at 5% and expressed in 2012 Canadian dollars. For mcrc patients with KRAS wild-type disease, the treatment strategy of bevacizumab plus folfiri was found to dominate the other two first-line treatment strategies. Sensitivity analyses revealed that the incremental cost-effectiveness ratio values were sensitive to the effectiveness of treatment, the costs of bevacizumab and cetuximab, and health utility values. Evidence from Ontario showed that bevacizumab plus folfiri is the cost-effective first-line treatment strategy for patients with KRAS wild-type mcrc. The panitumumab plus folfiri and cetuximab plus folfiri options were both dominated, but the cetuximab plus folfiri strategy must be further investigated given that, in the sensitivity analyses, the cost-effectiveness of that strategy was found to be superior to that of bevacizumab plus folfiri under certain ranges of parameter values.

A Randomized Phase II Trial of Vismodegib versus Placebo with FOLFOX or FOLFIRI and Bevacizumab in Patients with Previously Untreated Metastatic Colorectal Cancer

Vismodegib, a Hedgehog pathway inhibitor, has preclinical activity in colorectal cancer (CRC) models. This trial assessed the efficacy, safety, and pharmacokinetics of adding vismodegib to first-line treatment for metastatic CRC (mCRC). Patients were randomized to receive vismodegib (150 mg/day orally) or placebo, in combination with FOLFOX or FOLFIRI chemotherapy plus bevacizumab (5 mg/kg) every 2 weeks until disease progression or intolerable toxicity. The primary endpoint was progression-free survival (PFS). Key secondary objectives included evaluation of predictive biomarkers and pharmacokinetic drug interactions. A total of 199 patients with mCRC were treated on protocol (124 FOLFOX, 75 FOLFIRI). The median PFS hazard ratio (HR) for vismodegib treatment compared with placebo was 1.25 (90% CI: 0.89-1.76; P = 0.28). The overall response rates for placebo-treated and vismodegib-treated patients were 51% (90% CI: 43-60) and 46% (90% CI: 37-55), respectively. No vismodegib-associated benefit was observed in combination with either FOLFOX or FOLFIRI. Increased tumor tissue Hedgehog expression did not predict clinical benefit. Grade 3 to 5 adverse events reported for more than 5% of patients that occurred more frequently in the vismodegib-treated group were fatigue, nausea, asthenia, mucositis, peripheral sensory neuropathy, weight loss, decreased appetite, and dehydration. Vismodegib did not alter the pharmacokinetics of FOLFOX, FOLFIRI, or bevacizumab. Vismodegib does not add to the efficacy of standard therapy for mCRC. Compared with placebo, treatment intensity was lower for all regimen components in vismodegib-treated patients, suggesting that combined toxicity may have contributed to lack of efficacy.

629 - Different Clinical Outcome of Metastatic Colorectal Cancer (MCRC) Patients Treated with Intensive Triplet Chemotherapy Plus Bevacizumab (FIR-B/FOX) According to Kras Genotype and Disease Extension

ABSTRACT Background Bevacizumab (BEV) plus triplet chemotherapy can increase efficacy of first-line treatment of MCRC (Bruera G et al, BMC Cancer 2010, 10:567), particularly if integrated with secondary liver surgery in liver-limited (L-L) patients (pts) (Bruera G et al, Clin Colorectal Cancer 2012). Clinical outcome of FIr-B/FOx regimen was evaluated according to KRAS genotype in L-L and other MCRC pts. Methods Tumoral and metastatic samples were screened for KRAS codon 12 and 13, and BRAF mutations by SNaPshot and/or direct sequencing. MCRC pts were classified as L-L and other or multiple metastatic (O/MM). Activity and efficacy were evaluated and compared using log-rank test. Results Fifty-nine pts were evaluated: 31 KRAS wild-type, 53%; 28 KRAS mutant, 47%. At 21.5 months median follow-up, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were, respectively: KRAS wild-type 90%, 14 months, 38 months; KRAS mutant 67%, 11 months, 20 months. PFS and OS were, respectively: overall in 25 L-L compared to 32 O/MM evaluable pts, 17 and 12 months, 47 and 21 months, significantly different; in KRAS wild-type, 12 L-L compared to 18 O/MM, 21 and 12 months, 47 and 28 months, significantly different; in KRAS mutant, 13 L-L compared to 14 O/MMS, 11 months equivalently, 39 and 19 months, not significantly different. Conclusion First line FIr-B/FOx regimen can increase activity and efficacy of KRAS wild-type and mutant MCRC pts; integration with secondary liver surgery significantly discriminates increased clinical outcome in KRAS wild-type L-L compared to O/MM pts while not in KRAS mutant pts. Disclosure All authors have declared no conflicts of interest.

A Randomised Controlled Phase II Trial of the Combination of XELOX with Thalidomide for the First-line Treatment of Metastatic Colorectal Cancer.

ObjectiveTo evaluate the efficacy and safety of the combination of XELOX regimen (oxaliplatin plus capecitabine) with thalidomide for the first-line treatment of metastatic colorectal cancer (MCRC).MethodsAll of the 89 patients with MCRC who fulfilled eligibility criteria were randomly assigned to treatment group (n=44) and control group (n=45). The treatment group received a combination of XELOX with thalidomide and the control group received XELOX alone. Each patient received at least 2 cycles of treatment (1 cycle=21 d). The primary endpoint was progression-free survival (PFS) and the secondary endpoints were objective response rate (ORR) as well as disease control rate (DCR). Drug safety and quality of life were also assessed.ResultsThe median PFS of the treatment and control groups were 5.6 and 5.2 months, respectively. The difference did not have a statistical significance (P=0.307). The ORRs of the two groups also had no statistical difference (34.1% vs. 26.7%, P=0.446). The addition of thalidomide to XELOX significantly improved the DCR (63.6% vs. 42.2%, P=0.043). Among 24 patients with hepatic metastasis in the treatment group, 2 patients satisfied the surgical criteria after treatment but none of 23 patients in the control group did. Grade 3 or 4 constipation in patients treated with thalidomide was significantly increased (20.5% vs. 4.4%, P=0.022) but didn’t result in treatment interruption. The rate of lethargy was increased but the difference between the two groups had no statistical significance (13.6% vs. 4.4%, P=0.130). The quality of life had no statistical difference between the two groups.ConclusionsThe combination of XELOX with thalidomide for the first-line treatment of MCRC was well tolerated. Statistically significant improvement was achieved for the DCR but not for PFS.

Different clinical outcome of metastatic colorectal cancer (MCRC) patients treated with intensive triplet chemotherapy plus bevacizumab (FIr-B/FOx) according to KRAS genotype and disease extension.

e14010 Background: Bevacizumab (BEV) plus triplet chemotherapy can increase efficacy of first-line treatment of MCRC, particularly if integrated with secondary liver surgery in liver-limited (L-L) patients (pts). Clinical outcome of FIr-B/FOx regimen was evaluated according to KRAS genotype in L-L and other MCRC pts. Methods: Tumoral and metastatic samples were screened for KRAS codon 12 and 13, and BRAF mutations by SNaPshot and/or direct sequencing. MCRC pts were classified as L-L and other or multiple metastatic (O/MM). Activity and efficacy were evaluated and compared using log-rank test. Results: Fifty-nine pts were evaluated: 31 KRAS wild-type, 53%; 28 KRAS mutant, 47%. At 21.5 months median follow-up, objective response rate (ORR), progression-free survival (PFS) and overall survival (OS) were, respectively: KRAS wild-type 90%, 14 months, 38 months; KRAS mutant 67%, 11 months, 20 months. PFS and OS were, respectively: overall in 25 L-L compared to 32 O/MM evaluable pts, 17 and 12 months, 47 and 21 months, significantly different; in KRAS wild-type, 12 L-L compared to 18 O/MM, 21 and 12 months, 47 and 28 months, significantly different; in KRAS mutant, 13 L-L compared to 14 O/MMS, 11 months equivalently, 39 and 19 months, not significantly different. Conclusions: First line FIr-B/FOx regimen can increase activity and efficacy of KRAS wild-type and mutant MCRC pts; integration with secondary liver surgery significantly discriminates increased clinical outcome in KRAS wild-type L-L compared to O/MM pts while not in KRAS mutant pts.

Long-term follow-up of a multicenter phase II study of chemo-immunotherapy in the treatment of metastatic colorectal cancer (MCC).

536 Background: The combination of low-dose interleukin-2 (IL-2) and 13-cis retinoic acid (RA) has been shown to decrease vascular endothelial growth factor (VEGF) of patients with MCC (Anticancer Res, 2005). Moreover, results of various studies have shown that the addition of IL-2 and RA to chemotherapy (CT) increased treatment efficacy, inducing a statistically significant decrease of VEGF, with a low cost. Methods: Patients with MCC, deemed unresectable, were given the following treatment for two consecutive days (D1-D2): Oxaliplatin 50 mg/m2, Leucovorin (LV), 200 mg/m2, 5-fluorouracil (5-FU) 400 mg/m2, Capecitabine (C) 2,000 mg/m2 (FOCFOX). After 2 weeks Camptothecin, 90 mg/m2 (D1-D2), was administered with the same doses of LV, 5-FU and C (FOCFIRI) as first-line treatment of MCC. Subcutaneous IL-2 1.8 x 106 I.U. and oral RA, 0.5 mg/kg were given 5 days/week. Induction CT was administered for 12 courses, alternating FOCFOX and FOCFIRI, followed by maintenance treatment with the same schedule of IL-2 + RA, for 3 weeks/month. The primary endpoint was the decrease ≥ 30% of VEGF of patients with MCC. Secondary endpoints were the cost of IL-2 and RA with respect to bevacizumab, toxicity, progression- free survival (PFS), and overall survival (OS). Results: From 08/2000 to 08/2006, fifty-four patients with MCC were entered into the trial. After a median follow up of 64 months (95% CI 62-85%), a statistically significant > 30% (p<0.001) decrease of VEGF was observed. Costs of therapy were $ 304.00/month for IL-2/RA and $ 1,700.00/month for bevacizumab (82% cost reduction). The most common adverse events of CT were grade 3/4 neutropenia, leukopenia, thrombocythopenia, and anemia in 33%, 9%, 2%, and 2% of patients, respectively, peripheral neuropathy in 10% of patients. Mild cutaneous skin rash, fever and autoimmune reactions were observed in the patients who received the maintenance immunotherapy. PFS at 10 months was 76% (95% CI 62-86). Median PFS was 27.8 months, while median OS was 48.8 months. Conclusions: These data show that maintenance immunotherapy with low-dose IL-2 and oral RA in patients with MCC has a low toxicity profile, is cost effective, decrease VEGF and seems to improve expected PFS and OS. No significant financial relationships to disclose.

Capecitabine plus oxaliplatin (XELOX) versus 5‐fluorouracil/leucovorin plus oxaliplatin (FOLFOX‐6) as first‐line treatment for metastatic colorectal cancer

A regimen consisting of 5-fluorouracil/leucovorin plus oxaliplatin (FOLFOX-6) is widely used in France in the first-line treatment of metastatic colorectal cancer (MCRC). The aim of our study was to demonstrate the non-inferiority of capecitabine plus oxaliplatin (XELOX) versus FOLFOX-6 for this indication. Patients were randomly assigned to receive XELOX or FOLFOX-6 for 6 months. The primary endpoint was overall response rate (ORR) in the per-protocol (PP) population; however, progression-free and overall survival (OS), time to response and response duration were also assessed. A total of 306 patients were enrolled (XELOX n = 156; FOLFOX-6 n = 150). ORR was 42 and 46% with XELOX and FOLFOX-6, respectively, in the PP population. The difference between groups was 4.7%; the upper limit of the unilateral 95% confidence interval (14.4%) was below the non-inferiority margin of 15%. In the intent-to-treat population, median progression-free survival was 8.8 months with XELOX and 9.3 months with FOLFOX-6, and median OS was 19.9 and 20.5 months, respectively. XELOX patients had significantly more grade 3/4 thrombocytopenia (12% vs. 5%) and diarrhoea (14% vs. 7%), but significantly less grade 3/4 neutropenia (5% vs. 47%), febrile neutropenia (0% vs. 6%) and neuropathy (11% vs. 26%) than FOLFOX-6 patients. We conclude that XELOX is non-inferior in terms of efficacy to FOLFOX-6 in the first-line treatment of MCRC, but has a different toxicity profile.

Differences in Efficacy and Safety Between Capecitabine and Infusional 5-Fluorouracil When Combined With Irinotecan for the Treatment of Metastatic Colorectal Cancer

Capecitabine is an oral fluoropyrimidine that is shown to have similar efficacy to 5-fluorouracil (5-FU) when used both alone and in combination with oxaliplatin in the treatment of colorectal cancer (CRC). Capecitabine and irinotecan combinations (XELIRI) have been developed for the treatment of this disease but randomized comparisons with standard infusional 5-FU and irinotecan (FOLFIRI) showed conflicting results. We searched the literature for randomized controlled trials comparing XELIRI to FOLFIRI for the treatment of metastatic colorectal cancer. Odds ratios with 95% confidence intervals were used to analyze dichotomous variables. Hazard ratios for progression and death were combined with an inverse variance method based on logarithmic conversion. The fixed-effect model and Mantel-Haenszel method were used. Heterogeneity was investigated with the Q-test and I2. Sensitivity analyses were performed. Only 3 studies were identified, involving a total of 450 patients. XELIRI was associated with significantly shorter progression-free survival (PFS) and increased grade 3/4 gastrointestinal toxicities such as nausea, vomiting, and diarrhea. Severe neutropenia, however, was significantly more frequent with FOLFIRI. No differences in responses and febrile neutropenia events were observed. Our analysis suggest that the 2 regimens are not equivalent. XELIRI remains an option for the first-line treatment of metastatic CRC but FOLFIRI should be preferred as it confers more benefits in terms of PFS and induces fewer GI toxicities.

The efficacy of Fufangbanmao capsules combined with chemotherapy in the treatment of patients with metastatic colorectal cancer

Objective To investigate the efficacy and side effects of Fufangbanmao capsules combined with FOLFOX-4 (Oxaliplatin + 5-fluorouracil /Calcium folinate) regimen in the treatment of metastatic colorectal cancer (MCC). Methods A total of 107 patients with previously untreated MCC, who were admitted to the hospital between April 2006 and October 2008, were randomly divided into combination group (n = 54) and chemotherapy group (n = 53). In combination group, patients received Fufangbanmao capsules (750 mg twice daily) and FOLFOX4 regimen (oxaliplatin 85 mg/m2 day 1, infusion of CF 200 mg/m2 for 2 hours followed by bolus 5-FU 400 mg/m2 and a 22-hour infusion of 5-FU 600 mg/m2 ). Whereas the patients in chemotherapy group were treated with FOLFOX4 regimen. Results The effective rate was 44. 4% in combination group and 37. 7% in chemotherapy group with no significant difference (P = 0. 481). The median time to progression (TTP) was 11. 6 and 7. 9 months in combination group and chemotherapy group, respectively, with significant difference (P=0. 020). The difference was found in improvement of quality of life (QOL) between combination group and chemotherapy group (57. 4% vs 32. 1 % , P=0. 008). The side effects in two groups included gastrointestinal toxicities, neuropathy, alopecia and bone marrow suppression. However, Ⅲ/Ⅳ neutropenia was significantly less in combination group(37. 0%) when compared with chemotherapy group (58. 5%, P = 0. 043). Conclusions In first-line treatment of MCC, Fufangbanmao capsules combined with FOLFOX4 regimen showed synergic and enhanced effect for improving TTP and QOL, and also reduced the incidence of neutropenia. Key words: Colorectal neoplasms; Mylabris; Antineoplastic combined chemotherapy protocols; Neoplasm metastasis

Capecitabine in combination with irinotecan (XELIRI), administered as a 2-weekly schedule, as first-line chemotherapy for patients with metastatic colorectal cancer: a phase II study of the Spanish GOTI group

Background:Combination chemotherapy is standard treatment for metastatic colorectal cancer (MCRC). The aim of this study was to determine the efficacy and safety of capecitabine+irinotecan (2-weekly schedule), as first-line therapy of MCRC.Methods:Patients received irinotecan 175 mg m−2 on day 1 and oral capecitabine 1000 mg m−2 twice daily on days 2–8 every 2 weeks. For patients aged ⩾65 years, the starting doses of irinotecan and capecitabine were reduced to 140 and 750 mg m−2, respectively.Results:A total of 53 patients were enrolled: 29 (55%) were ⩾65 years old. In an intention-to-treat analysis, complete response was achieved in three patients for an overall response rate (ORR) of 32%. The disease control rate (ORR + stable disease) was 66% and the median duration of response was 7.3 months. Median time to progression and overall survival were 9.0 and 19.2 months, respectively. Grade 4 neutropenia was reported in one patient: no other grade 4 toxicities were recorded. Grade 3 diarrhoea occurred in 8 (15%) patients and grade 1–2 hand–foot syndrome in 7 (13%) patients.Conclusion:Capecitabine and irinotecan, given every 2 weeks, as first-line treatment of MCRC is an active regimen with a manageable toxicity profile, even in older patients.

6052 Capecitabine single agent or in combination in the routine first-line treatment of a predominantly elderly population with metastatic colorectal cancer (MCRC)

5-Fluorouracil (5-FU) plus leucovorin (LV) has been the mainstay of treatment for colorectal cancer (CRC), with infused schedules more widely adopted in Europe and bolus schedules preferred in North America. However, the effective, oral fluoropyrimidine capecitabine is increasingly replacing intravenous (IV) 5-FU/LV on both sides of the Atlantic. Capecitabine generates 5-FU preferentially in tumor and is a well-established, first-line treatment for metastatic CRC. In this setting, capecitabine achieves a superior response rate, at least equivalent time to disease progression (TTP) and overall survival, and favorable safety compared with bolus 5-FU/LV. The benefits of capecitabine have been transfered into the adjuvant setting. Recent data from a large, international, randomized trial (Xeloda Adjuvant Chemotherapy Trial [X-ACT]) confirm that capecitabine (Xeloda, Roche Laboratories, Nutley, NJ) achieves favorable safety versus 5-FU/LV (Mayo Clinic regimen) and is at least as effective as IV 5-FU/LV in the adjuvant treatment of patients with resected stage III colon cancer. Capecitabine is also an effective and well-tolerated combination partner for oxaliplatin (XELOX) and irinotecan (XELIRI), achieving high efficacy with a good safety profile. An extensive phase III clinical trial program is further establishing the potential of the simplified capecitabine combinations to improve outcomes and unify treatment practices in the metastatic and adjuvant settings. New combinations with novel agents such as capecitabine/oxaliplatin plus erlotinib or bevacizumab are currently under investigation. Capecitabine has also shown promising activity and good tolerability in combination with radiotherapy in rectal cancer.

Bevacizumab (Bev), irinotecan (IRI), folinic acid (FA), and 5-fluorouracil (FU) every 2 weeks (BIFF regimen) as first-line treatment for metastatic colorectal cancer (MCRC) patients (pts): The SICOG experience

e15067 Background: The IRIFAFU regimen produced in MCRC pts a consistent activity (RR, 33% [95% CI, 27–39%], PFS, 7.4 [95% CI, 6.5–8.3] mo.) in 2 consecutive randomized SICOG trials . Bev was proven to significantly improve the efficacy of IFL regimen. Here we report the safety and activity results of the BIFF regimen as first-line treatment of MCRC. Patients: From Feb 2007 to Jul 2008, 95 pts with MCRC were treated: so far, 85 pts were evaluated for safety: M/F were 47/38, median age (range) was 64 (35–78) yrs. Fifty-six pts had a colon, and 29 pts a rectal carcinoma. ECOG PS was 0 (63 pts, 74%), or 1 (22 pts, 26%). Thirty-four (40%) pts had 1 site, 33 (39%) 2 sites, and 18 (21%) pts ≥3 sites of disease. Liver was involved in 66 (78%), lung in 23 (24%) pts. Twenty-one (25%) pts had an unresected primary (colon 13, rectum 8). Bev 5 mg/kg (1-h), and IRI 180 mg/sqm (1-h) were given IV on day 1, 6S-FA 250 mg/sqm (2-h), and FU 850 mg/sqm (bolus) were given IV on day 2 biweekly for a maximum of 12 cycles. Bev was continued until progression, severe toxicity, or refusal. Results: A median of 9 (range, 1–12) cycles of BIFF were delivered. G4 hematologic toxicity was: neutropenia (21%), and febrile neutropenia (10%). G≥3 non-hematologic toxicity was: diarrhea 15%, vomiting 7%, stomatitis 4%, hypertension 1%. No severe episodes of bleeding were registered. Among 81 assessable pts, 5 CRs (3 in liver, 1 in liver & nodes, 1 in liver & lung), and 41 PRs were registered, giving a RR of 57% (95% CI, 45–68%). Overall, 71/81 (88%, 95% CI, 77–93%) pts obtained a disease control. Liver mets resection, or primary resection, was safely performed in 3 pts and in 2 pts, respectively. After a median follow- up of 12 (range, 6–24) mo., median FFS was 8.4 (95% CI, 6.8–10.0), and median PFS was 14.1 (95% CI, 9.6–18.6) mo. With only 14 deaths, OS results are still immature. Conclusions: Unexpected side effects of the BIFF regimen were not registered. Addition of Bev increased the activity without worsening the tolerability of IRIFAFU combination as compared with our previous experience. Efficacy of BIFF was comparable with that reported with other Bev plus IRI-based combinations. Updated follow-up will be presented. No significant financial relationships to disclose.

Updated phase II study results of capecitabine (X) + irinotecan (I) + bevacizumab (A) as first-line therapy for metastatic colorectal cancer (MCRC)

e15064 Background: The oral fluoropyrimidine X has improved efficacy, safety, and convenience vs. 5-FU/LV in MCRC [Van Cutsem et al. Br J Cancer 2004] and early-stage colon cancer [Twelves et al. NEJM 2005]. A recent study showed that I + X q2w is active and well tolerated [Garcia-Alfonso et al. ESMO 2006]. The humanized monoclonal antibody A targets VEGF and limits tumor angiogenesis. The addition of A to 5-FU/LV/I (IFL regimen) improves survival significantly in patients (pts) with MCRC [Hurwitz et al. NEJM 2004]. Replacing 5-FU/LV with X in this combination is a logical step forward. Here we report data from an open-label phase II trial of XIA in MCRC. Methods: Pts with untreated, histologically confirmed MCRC received I 175mg/m2 i.v. d1, X 1,000 mg/m2 orally bid d2–8, and A 5 mg/m2 d1. Treatment was repeated q2w x 12 cycles in the absence of progressive disease (PD) or unacceptable toxicity. Pts without PD after 12 cycles of XIA continued on the same dose of A + X 1,500 mg/m2 bid d2–8, q2w. The primary endpoint was progression-free survival (PFS); secondary endpoints were overall response rate (ORR, RECIST), overall survival (OS), safety, and quality of life. Results: 57 pts have been enrolled. Baseline characteristics: M/F 44%/56%; median age 52 years (range 30–70); disease stage at initial diagnosis II/III/IV 16%/9%/75%; no. of metastatic sites 1/>1 47%/53%; most common metastatic site liver. Pts received a median 12 cycles (range 1–12) of XIA. All 57 pts are evaluable for safety and 56 for efficacy. ORR is 46% (3 CR, 13 PR); 5 pts (22%) have stable disease and 35 have PD. Median PFS and OS are 14.9 months (range 1.7–39.2) and 18.3 months (range 2.9–39.2), respectively. Grade 3 adverse events occurring in more than 1 pt are diarrhea (9%), hypertension (9%), hand-foot syndrome (7%), ileus (4%), and hypertriglyceridemia (4%); there is one report of grade 4 leucopenia. Conclusions: The XIA combination appears to be highly active and well tolerated as first-line treatment for MCRC; further studies of XIA are warranted. [Table: see text]

Phase II study of biweekly XELOX (capecitabine and oxaliplatin) as first line chemotherapy in elderly patients with metastatic colorectal cancer

e15053 Background: Analysis of efficacy and toxicity of biweekly XELOX as first line monotherapy in elderly patients (pts) with metastatic colorectal cancer (MCRC), based in results of W. Scheithauer (J Clin Oncol 2003; 21: 1307). Methods: From March/06 to November/08, 28 chemonaïve elderly pts (>75 years old) with MCRC, PS: 0–2, and adequate renal, hepatic and bone marrow functions, were included in a phase II study of: oxaliplatin 85 mg/ m2/ day 1 plus capecitabine 2000/ m2/ in 2 divided doses/ days 1–7 every 2 weeks. Treatment was continued until 12 cycles, tumour progression or innaceptable toxicity. Response evaluation every 6 cycles and toxicity every cycle was performed. At present 28 pts for toxicity and 24 pts for response are evaluable. Results: Median age: 78.2 years (range: 73.5–79.5). Male/Female: 14/14. Rectal/Colon: 9/19. Metastatic sites 1/2/>2: 15/6/6. Liver 78.6%, Lung 32.1%, Local tumour 7.1%, Retroperitoneum 14.2%, Peritoneum 10.7%. and Bones 7.1 %. Previous adjuvant with 5-FU regimens to 4 pts. Comorbidity grade by Charlson index 0–1/2/>2: 60.8%/ 28.6% / 10.7%, respectively. Median number of cycles for oxaliplatin and capecitabine were 8 (5.25–12) and 8 (5.25–11.75). Response rate: 2 pts complete response (8.3%), 8 pts partial response (33.3%),10 pts stable disease (41.7 %) and 4 pts progression (16.7%). The main CTC toxicity was Asthenia G2+3 in 6 (21.5%), Nausea and emesis G2 in 7 (25%), Diarrhea G2+3 in 7 (25%) and Hand-foot syndrome G1+2 in 5 pts (17.8%). No G4 toxicity or toxic deaths were observed. Median time to progression was 8.6 months.Median overall survival will be given updated at the congress. Conclusions: Preliminary results suggest that bi-weekly XELOX is an effective first line treatment for MCRC in elderly pts with an acceptable toxicity profile (especial surveillance of diarrhea is necessary) and protocol cumpliment. Combination with bevacizumab should be considered. No significant financial relationships to disclose.