Metastatic Colorectal Cancer

Following the discovery that mutant KRAS is associated with resistance to anti-epidermal growth factor receptor (EGFR) antibodies, the tumours of patients with metastatic colorectal cancer are now profiled for seven KRAS mutations before receiving cetuximab or panitumumab. However, most patients with KRAS wild-type tumours still do not respond. We studied the effect of other downstream mutations on the efficacy of cetuximab in, to our knowledge, the largest cohort to date of patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab plus chemotherapy in the pre-KRAS selection era.1022 tumour DNA samples (73 from fresh-frozen and 949 from formalin-fixed, paraffin-embedded tissue) from patients treated with cetuximab between 2001 and 2008 were gathered from 11 centres in seven European countries. 773 primary tumour samples had sufficient quality DNA and were included in mutation frequency analyses; mass spectrometry genotyping of tumour samples for KRAS, BRAF, NRAS, and PIK3CA was done centrally. We analysed objective response, progression-free survival (PFS), and overall survival in molecularly defined subgroups of the 649 chemotherapy-refractory patients treated with cetuximab plus chemotherapy.40·0% (299/747) of the tumours harboured a KRAS mutation, 14·5% (108/743) harboured a PIK3CA mutation (of which 68·5% [74/108] were located in exon 9 and 20·4% [22/108] in exon 20), 4·7% (36/761) harboured a BRAF mutation, and 2·6% (17/644) harboured an NRAS mutation. KRAS mutants did not derive benefit compared with wild types, with a response rate of 6·7% (17/253) versus 35·8% (126/352; odds ratio [OR] 0·13, 95% CI 0·07–0·22; p<0·0001), a median PFS of 12 weeks versus 24 weeks (hazard ratio [HR] 1·98, 1·66–2·36; p<0·0001), and a median overall survival of 32 weeks versus 50 weeks (1·75, 1·47–2·09; p<0·0001). In KRAS wild types, carriers of BRAF and NRAS mutations had a significantly lower response rate than did BRAF and NRAS wild types, with a response rate of 8·3% (2/24) in carriers of BRAF mutations versus 38·0% in BRAF wild types (124/326; OR 0·15, 95% CI 0·02–0·51; p=0·0012); and 7·7% (1/13) in carriers of NRAS mutations versus 38·1% in NRAS wild types (110/289; OR 0·14, 0·007–0·70; p=0·013). PIK3CA exon 9 mutations had no effect, whereas exon 20 mutations were associated with a worse outcome compared with wild types, with a response rate of 0·0% (0/9) versus 36·8% (121/329; OR 0·00, 0·00–0·89; p=0·029), a median PFS of 11·5 weeks versus 24 weeks (HR 2·52, 1·33–4·78; p=0·013), and a median overall survival of 34 weeks versus 51 weeks (3·29, 1·60–6·74; p=0·0057). Multivariate analysis and conditional inference trees confirmed that, if KRAS is not mutated, assessing BRAF, NRAS, and PIK3CA exon 20 mutations (in that order) gives additional information about outcome. Objective response rates in our series were 24·4% in the unselected population, 36·3% in the KRAS wild-type selected population, and 41·2% in the KRAS, BRAF, NRAS, and PIK3CA exon 20 wild-type population.While confirming the negative effect of KRAS mutations on outcome after cetuximab, we show that BRAF, NRAS, and PIK3CA exon 20 mutations are significantly associated with a low response rate. Objective response rates could be improved by additional genotyping of BRAF, NRAS, and PIK3CA exon 20 mutations in a KRAS wild-type population.Belgian Federation against Cancer (Stichting tegen Kanker).

Background: As we previously reported the GONO-FOLFOXIRI regimen compared to FOLFIRI demonstrated significant improvements in responses (60% vs 34%, p<0.001), secondary radical (R0) resection of metastases (15% vs 6%, p=0.03), progression-free survival (9.8 vs 6.9 months, p=0.006) and overall survival (22.6 vs 16.7 months, p=0.03) after a median follow up of 18.4 months. Methods: We updated overall survival (OS) and progression-free survival (PFS) data of the 244 randomized patients after a median follow up of 60.6 months (mos) and we used a risk-stratified analysis according to the Kohne prognostic model to determine if treatment outcomes differ in specific patient subgroups. Results: The updated results confirm a significant improvement for FOLFOXIRI in terms of PFS (median 9.8 vs 6.8 mos, HR=0.59, p<0.0001) and OS (median 23.4 vs 16.7 mos, HR=0.74, p=0.026 and 5-years survival rate 15% vs 8%). There is a PFS and OS benefit from FOLFOXIRI also excluding from the analysis the R0 patients (median PFS 9.5 vs 6.6 mos, p=0.0001 and median OS 20.2 vs 15.9 months, p=0.12). With regard to the risk-stratified analysis, FOLFOXIRI results in longer PFS and OS than FOLFIRI in all risk subgroups with Hazard Ratios for low, intermediate and high risk groups respectively of 0.68, 0.56 and 0.44 for PFS and of 0.90, 0.58 and 0.78 for OS. Conclusions: These results demonstrate that the GONO-FOLFOXIRI regimen is associated also with a better long term outcome compared to FOLFIRI (with an absolute benefit in survival at 5 years of 7%) and that the superiority of FOLFOXIRI is not only related to the increased rate of R0 surgery of metastases, but also to a better palliative effect which does not seem to be limited to some specific subgroup.

Over the past two decades, the treatment outcomes in metastatic colorectal cancer (mCRC) have been remarkably improved, largely from the evolution of systemic therapy. Also, the molecular biomarkers have played a major role in this improvement by their predictive value in current treatment paradigm in mCRC. Currently, extended RAS mutation analysis is required for consideration of anti-epidermal growth factor receptor therapy in patients with mCRC. Several uncommon gene alterations have emerged as the potential targets for their matched molecular targeted therapy. Although, most patients with mCRC do not derive benefit from immunotherapy. By using microsatellite instability or mismatch repair test, we are now able to identify a small subgroup of patients with mCRC who have a very good response to immune checkpoint inhibitors. With the increasing number of required biomarkers in mCRC management, multiplex gene panel testing is now replacing single gene testing strategy. In patients accessible to matched molecular targeted therapy, especially for clinical trials, the comprehensive genomic profiling might be the preferred testing method. Although, it is potentially benefit in mCRC treatment, the liquid biopsy is not yet clinically applicable. The optimal utilization of molecular biomarker testing is required for best treatment outcomes in individual patients.

Purpose: Recent studies have found that KRAS mutations predict resistance to monoclonal antibodies targeting the epidermal growth factor receptor in metastatic colorectal cancer (mCRC). A polymorphism in a let-7 microRNA complementary site (lcs6) in the KRAS 3# untranslated region (UTR) is associated with an increased cancer risk in non-small-cell lung cancer and reduced overall survival (OS) in oral cancers. We tested the hypothesis whether this polymorphism may be associated with clinical outcome in KRAS wild-type (KRASwt) mCRC patients treated with cetuximab monotherapy.

Colorectal cancer (CRC) is common in North America. Metastatic disease is present at diagnosis in 30% of the patients, and approximately half of early-stage patients will eventually present with metastatic disease. Until recently, few chemotherapy options were available to treat metastatic CRC. The authors review the results of recent clinical trials and the design of ongoing trials in the management of patients with metastatic colorectal cancer. Fluorouracil (5-FU) with leucovorin (LV) modulation has a marginal but positive effect on survival in those patients. The recent incorporation of irinotecan (CPT-11) and oxaliplatin for the management of advanced CRC has generated further improvement in survival. The development of oral fluoropyrimidines, mimicking continuous infusion 5-FU, is convenient. In randomized trials, capecitabine was equally effective to bolus 5-FU and LV in the management of metastatic CRC. Recently completed or ongoing clinical trials to study novel targeting ag...

To examine whether surgical resection of the primary tumour confers a survival benefit and to identify the predictive factors of outcome in patients presenting with asymptomatic metastatic colorectal cancer (CRC).A review of a hospital database in a tertiary institution over a 6-year period (1999–2005) revealed 70 patients with asymptomatic primary CRC and unresectable liver metastases treated initially by systemic chemotherapy. A multivariate regression analysis model was used to determine the relative influence of multiple tumours, single/multiple liver metastases, tumour site, differentiation, response of liver and primary tumour to chemotherapy, biochemical response to chemotherapy, age at presentation, performance status and surgical intervention for the CRC primary.In 67 cases (3 lost to follow-up), 63 had multiple and 4 single surgically irresectable liver metastases. A total of 41 deaths were recorded. All patients received systemic chemotherapy and surgery was performed for bowel obstruction, bleeding or stable disease (n = 32). Surgery (OR 0.26; p = 0.00013) and clinical response of the primary tumour (OR 0.53; p = 0.012) were independently associated with prolonged survival. Proximal tumours (OR 2.61; p = 0.0075) and multiple primaries (OR 3.37; p = 0.02) were associated with poor outcome.Surgical resection and response of the primary tumour to chemotherapy may be associated with improved survival, but proximal or multiple cancers predict poor outcome in patients with asymptomatic CRC and unresectable metastatic disease.

PurposeRecent advances in the management of colorectal cancer have improved the quality of life and the survival of patients treated with chemotherapy. In order to define the contribution of chemotherapy in elderly patients, we studied the tolerance and the efficacy of first-line chemotherapy in patients with metastatic colorectal cancer.

Purpose The present study analyzed the polymorphisms of apoptosis-related genes and their impact on the response to chemotherapy and survival of patients with colorectal cancer. Patients and methods A total of 76 patients with recurrent or metastatic colorectal cancer treated with capecitabine and oxaliplatin (XELOX) combination chemotherapy were enrolled in the present study. The single nucleotide polymorphisms of 15 apoptosis-related genes (TP53, BCL2L, TNFRSF10B, AKT1, PTGS2/COX2, BID, RIPK1, FAS, FASL, caspase 3, and caspase 6-10) were determined using a PCR-RFLP assay.

Purpose: To provide oncology nurses with an overview of the toxicity management associated with the anti-epidermal growth factor receptor (EGFR) monoclonal antibodies cetuximab and panitumumab in patients with metastatic colorectal cancer. Methods: Monoclonal antibodies such as cetuximab and panitumumab that target EGFR have provided patients with metastatic colorectal cancer with effective treatment options. Both antibodies can be used as monotherapy; cetuximab is also approved for use in combination with chemotherapy. We reviewed the literature regarding the signs and symptoms, assessment of severity, and strategies available to prevent and manage adverse events associated with these agents. Key results: This class of therapeutics is associated with an overall acceptable adverse event profile that is distinctly different from conventional chemotherapeutics. In contrast to cytotoxic chemotherapy, which causes myelosuppression, mucositis, and nausea and vomiting, common toxicities reported for anti-EGFR therapy include the more frequent cutaneous toxicities, electrolyte imbalances, and diarrhoea, as well as the less frequent ocular toxicities. Infusion reactions are also observed with the chimerical monoclonal antibody cetuximab. Conclusions: Oncology nurses play a key role in the administration of multi-agent treatment regimens, especially with respect to the identification and management of toxicities, patient education, and patient support. By reducing the incidence and severity of the adverse events associated with anti-EGFR therapy, oncology nurses have the potential to sustain patient adherence to completion of treatment, identify signs and symptoms early, proactively manage adverse events, and provide appropriate treatment interventions, thereby improving patient quality of life.

Between July 2001 and September 2002, 49 eligible patients were enrolled in an open-label phase II study to assess the efficacy and safety of first-line treatment with capecitabine/irinotecan in metastatic colorectal cancer. Patients received capecitabine (1000 mg/m2 twice daily) on days 1-14 and irinotecan (240 mg/m2) on day 1 of a 21-day cycle. Patients enrolled had a median age of 64.5 years, and 6% of patients had an Eastern Cooperative Oncology Group performance status of 2. Fifty-seven percent of patients were male. Forty-two patients were evaluable for response. There was 1 complete response (2%), 18 partial responses (43%), 20 cases of stable disease (48%), and 3 cases of disease progression (7%), for an overall response rate of 45% (95% CI, 30%-60%). The median duration of response was 5.7 months (range, 2.5-II.3 months). Median survival was 13.4 months (range, 1.2-28.8 months) and median progression-free survival was 6.2 months (range, 1.2-17.5 months). At 1 year, the esti...

Irinotecan (CPT-11) is active against colorectal cancer (CRC) refractory to 5-fluorouracil. Further information is needed to confirm whether CPT-11 monotherapy is more effective against tumors than 5-FU monotherapy or if there is cross-resistance of CPT-11 with 5-FU. This study assessed the efficacy and toxicity of CPT-11 350 mg/m2 iv, once every 3 weeks, in patients with unsuccessfully pretreated advanced CRC.

The purpose of this study was to determine the tolerability and activity of rofecoxib (Vioxx ® ; Merck & Co., Inc., Whitehouse Station, NJ, http://www.merck. com) combined with weekly irinotecan (Camptosar ® ; Pfizer Pharmaceuticals, New York, http://www.pfizer. com) and infusional 5-fluorouracil (5-FU) as secondline therapy in metastatic colorectal cancer (MCRC). Enrolled patients had previously treated metastatic disease, were aged ≥18 to ≤75 years, and had adequate performance status. A cycle of treatment consisted of i.v. irinotecan on days 1, 8, 15, and 22, rofecoxib at an oral dose of 50 mg/day, and infusional 5-FU at a fixed dose of 200 mg/m 2 per day for 5 weeks followed by 3 weeks of therapy with rofecoxib alone. In the dose-finding study, the starting dose of irinotecan was 87.5 mg/m 2 and further dose escalations were planned by increments of 12.5 mg/m 2 up to 125 mg/m 2 . Forty-eight consecutive patients were enrolled in the study. Among the 15 cases enrolled in the dose-finding study, one patient experienced grade 3 reversible diarrhea as the dose-limiting toxicity, at the fourth dose level tested. Therefore, the dose of irinotecan for the phase II study was 125 mg/m 2 , and 33 patients were enrolled and received a total of 75 cycles. Hematological side effects were moderate, with grade 4 neutropenia recorded in only two patients. The most common nonhematological toxicity was diarrhea, occurring in 25 patients (75.8%) and considered to be of grade 3 in 12 patients (36.4%). Sixteen patients achieved partial responses (48.5%; 95% confidence interval [CI], 30.8%-66.5%), and another 10 patients (30.3%) had stable disease. The median time to progression was 7 months (95% CI, 5-12) and the median overall survival (OS) was 18 months; the 1-year estimated OS rate was 69.4%. The unique schedule tested in this study is feasible, is well-tolerated, and has promising activity in patients with MCRC after progression on oxaliplatin (Eloxatin ® ; Sanofi-Synthelabo Inc., New York, http:// www.sanofi-synthelabo.us)-based chemotherapy.

With recent advances in chemotherapy, traditional clinicopathological factors should not be used to exclude otherwise resectable patients from surgery. Pathological or clinical response to chemotherapy has become valuable in determining the treatment for individual patients. Portal vein embolization and two-stage operation with ablative therapy and preoperative chemotherapy should be considered for unresectable liver metastases located in a liver remnant that is at the minimum volume required for survival. The recent E0RTC 40983 trials regarding preoperative chemotherapy for resectable CLM have failed to demonstrate a clear significant advantage. However, patients with a low clinical risk score for the recurrence, such as several metastases of less than 4 cm, and who are fit candidates for liver resection are often offered immediate surgery. Patients at high clinical risk should also be considered for neoadjuvant chemotherapy. One forthcoming and appealing strategy is to adapt postoperative treatment according to tumor response as evaluated by neoadjuvant chemotherapy or by the presence of individual tumor biomarker such as the Kras mutation or singlenucleotide polymorphisms. This could avoid the overtreatment of nonresponsive patients and enable a more tailored approach to treat an individual patient's disease. The treatment paradigm for CLM is rapidly changing with the development of newer anticancer chemotherapeutic agents.

The table reports outcomes over a 10-year period. Results were driven by the impact of ICS on quality of life, rather than on mortality. Findings were stable over most input data ranges. However, at efficacy levels below 3% and toxicity rates greater than 2.9%, the cost-effectiveness estimate exceeded $100,000/QALY. CONCLUSION: Results suggest that inhaled steroids deliver good comparative value in mild-to-moderate adult asthma. More research is needed, however, on the impact of ICS toxicity on patient preferences.

The triple drug combination consisting of irinotecan, oxaliplatin and 5-fluorouracil (FOLFOXIRI) has demonstrated higher activity and efficacy compared to the doublet FOLFIRI. 5-Fluorouracil could be substituted in FOLFOXIRI regimen by capecitabine, an oral fluoropyrimidine with similar efficacy. Recently, a dose-finding trial has demonstrated the feasibility of the combination of irinotecan, oxaliplatin and capecitabine (XELOXIRI) and established their recommended doses. The aim of this study was to evaluate the activity of XELOXIRI. A total of 36 patients with unresectable metastatic colorectal cancer received irinotecan 165 mg m(-2) and oxaliplatin 85 mg m(-2) on day 1 plus capecitabine 2000 mg m(-2) per day orally in two doses from day 1 to day 7, every 2 weeks. Grade 3-4 toxicities were infrequent, expect for neutropenia and diarrhoea, which were each observed in 30% of patients. Two complete and twenty-two partial responses were obtained, corresponding to an overall response r...

Purpose We conducted a phase I/II clinical trial to determine the safety and feasibility of combining vorinostat with 5-fluorouracil (5-FU) in patients with metastatic colorectal cancer (mCRC) and elevated intratumoral thymidylate synthase (TS). Methods Patients with mCRC who had failed all standard therapeutic options were eligible. Intratumoral TS mRNA expression and peripheral blood mononuclear cell (PBMC) histone acetylation were measured before and after 6 consecutive days of vorinostat treatment at 400 mg PO daily. 5-FU/LV were given on days 6 and 7 and repeated every 2 weeks, along with continuous daily vorinostat. Dose escalation occurred in cohorts of three to six patients. Results Ten patients were enrolled. Three dose levels were explored in the phase I portion of the study. Two dose-limiting toxicities (DLTs) were observed at the starting dose level, which resulted in dose de-escalation to levels −1 and −2. Given the occurrence of two DLTs at each of the dose levels, we were unable to establish a maximum tolerated dose (MTD). Two patients achieved significant disease stabilization for 4 and 6 months. Grade 3 and 4 toxicities included fatigue, thrombocytopenia and mucositis. Intratumoral TS downregulation ≥50% was observed in one patient only. Acetylation of histone 3 was observed in PBMCs following vorinostat treatment. Conclusions The study failed to establish a MTD and was terminated. The presence of PBMC histone acetylation indicates biological activity of vorinostat, however, consistent reductions in intratumoral TS mRNA were not observed. Alternate vorinostat dose-scheduling may alleviate the toxicity and achieve optimal TS downregulation.

Over the past 10 years there has been a significant increase in the armamentarium of agents available for use in the treatment of advanced colorectal cancer (CRC). Among these new agents are two monoclonal antibodies targeting the epidermal growth factor receptor (EGFR): cetuximab, a mousehuman chimeric monoclonal antibody, and panitumumab, a fully human monoclonal antibody. Both are approved as monotherapy for the treatment of chemotherapy-refractory advanced CRC. Cetuximab is also indicated for use in combination with irinotecan. Here, we review 10 reports of phase II and III clinical studies of patients treated with panitu-mumab or cetuximab monotherapy. The clinical trials demonstrate similar efficacy profiles for advanced CRC patients treated with panitumumab and cetuximab monotherapy, with some differences in their adverse event profiles. In addition, the recent results of retrospective tumor KRAS gene mutational analyses in CRC patients treated with anti-EGFR monotherapy are reviewed. Data from the clinical trials reviewed here clearly demonstrate that anti-EGFR monotherapy is an effective treatment modality for patients with chemotherapy-refractory advanced CRC. The Oncologist

PURPOSE: This study was designed to investigate survival after curative resection of colorectal liver metastases in patients with expanded indications. METHODS: A total of 501 patients had 545 liver resections for metastatic colorectal cancer. There were no predefined criteria for resectability with regard to the number or size of the tumors, locoregional invasion, or extrahepatic disease, except that resection had potential to be complete and macroscopically curative. All patients who had curative hepatic resection were advised to start postoperative adjuvant chemotherapy. RESULTS: A total of 259 patients had expanded indications (52 percent), including 14 with liver metastases >10 cm, 194 with bilateral deposits, 140 with four or more liver metastases, and 73 with extrahepatic disease. The overall actuarial survival rates at one, three, five, and ten years were 88, 67, 45, and 36 percent, respectively, for patients with classic indications and 84, 53, 34, and 24 percent, respectively, for patients with expanded indications (P = 0.0009). In the group of expanded indications, there were more patients who received preoperative than postoperative chemotherapy: 72 (28 percent) vs. 18 (7 percent; P < 0.0001), and 148 (70 percent) vs. 131 (61 percent; P = 0.0466). In a multivariate analysis, four or more liver metastases and extrahepatic disease were independent predictors of poor outcome. Adjuvant chemotherapy significantly improved survival (P = 0.0002). CONCLUSIONS: This study suggested that liver resection should be indicated in patients with expanded indications. The extent of the benefits of preoperative and postoperative chemotherapy needs to be quantitated. [

For patients resistant to leucovorin (LV) and 5-¯uorouracil (5-FU), the addition of oxaliplatin (85 or 100 mg/m 2 ) to bimonthly LV±5-FU has given a response rate of 20±46%. The highest response rate has been observed with oxaliplatin 100 mg/m 2 (FOLFOX2). The present phase II study (FOLFOX6) infused oxaliplatin (100 mg/m 2 ) with LV (400 mg/m 2 ) as a 2-h infusion on day 1, followed by bolus 400 mg/m 2 and a 46-h infusion (2.4±3 g/m 2 ) of 5-FU, every 2 weeks. Among the 60 patients treated, 16 (27%) had partial responses (95% con®dence interval: 15±38), 27 (45%) had stable disease, 15 (25%) experienced disease progression and 2 (3%) had non-measurable disease. From the start of FOL-FOX6, median progression-free survival was 5.3 months and median survival 10.8 months. From the 448 cycles analysed, NCI-CTC grade 3±4 toxicities per patient were: peripheral neuropathy 16%, nausea 7%, diarrhoea 7%, mucositis 5%, neutropenia 24%, thrombocytopenia 2%. Overall 26 (46%) patients experienced grade 3±4 toxicities. Because of toxicity, only 36% of the patients received 90% of the scheduled oxaliplatin dose intensity. FOLFOX6 was active in pretreated patients resistant to LV±5-FU and is being investigated as ®rst-line therapy. We are now investigating FOLFOX7, a regimen with a higher oxaliplatin dose intensity and a lower 5-FU dose. #

Irinotecan is active against colorectal cancer in patients whose disease is refractory to fluorouracil. We investigated the efficacy of these two agents combined for first-line treatment of metastatic colorectal cancer.387 patients previously untreated with chemotherapy (other than adjuvant) for advanced colorectal cancer were randomly assigned open-label irinotecan plus fluorouracil and calcium folinate (irinotecan group, n=199) or fluorouracil and calcium folinate alone (no-irinotecan group, n=188). Infusion schedules were once weekly or every 2 weeks, and were chosen by each centre. We assessed response rates and time to progression, and also response duration, survival, and quality of life. Analyses were done on the intention-to-treat population and on evaluable patients.The response rate was significantly higher in patients in the irinotecan group than in those in the no-irinotecan group (49 vs 31%, p<0·001 for evaluable patients, 35 vs 22%, p<0·005 by intention to treat). Time to progression was significantly longer in the irinotecan group than in the no-irinotecan group (median 6·7 vs 4·4 months, p<0·001), and overall survival was higher (median 17·4 vs 14·1 months, p=0·031). Some grade 3 and 4 toxic effects were significantly more frequent in the irinotecan group than in the no-irinotecan group, but effects were predictible, reversible, non-cumulative, and manageable.Irinotecan combined with fluorouracil and calcium folinate was well-tolerated and increased response rate, time to progression, and survival, with a later deterioration in quality of life. This combination should be considered as a reference first-line treatment for metastatic colorectal cancer.

a maximum of 12 cycles, after which a maintenance program using cetuximab alone was allowed for a maximum of 6 months. Results: Eighty-two unselected patients were screened; 70 were EGFR+ and entered the trial. Of the 67 assessable patients, the objective response rate was 64.2% (95% CI: 52.5-75.5%) and the tumor growth control rate was 94% (95% CI: 88-99%). All the objective responses except 1 were confirmed. In the group of patients with initially unresectable liver disease alone, 7/33 (21%) were resected. The median time to progression (TTP) and overall survival (OS) were 10.0 and 22.0 months, respectively. The treatment was well tolerated, with no treatment-related deaths, while 24.2% of the patients were affected by cutaneous toxicity of grade 1 2. Mutational analysis of the KRAS and BRAF genes was retrospectively performed on 35 of the 69 patients treated with cetuximab (51%). KRAS was mutated in 13 out of the 35 cases (37%), whereas no mutations were detected in the BRAF gene. A trend toward an association between KRAS mutations and objective response to treatment (p = 0.07)

Background: 5-fluorouracil (5-FU), irinotecan, and oxaliplatin are the most active drugs in advanced colorectal cancer (CRC), and survival is improved with patient exposure to all of them.The efficacy and safety of an alternating schedule of continuous-infusion 5-FU with leucovorin (LV) plus oxaliplatin (ie, FOLFOX regimen) or irinotecan (ie, FOLFIRI regimen) was assessed in the first-line setting. Patients and Methods: Seventy-nine patients with previously untreated, unresectable CRC were included.Treatment consisted of 5-FU/LV (de Gramont schedule) plus oxaliplatin (85 mg/m 2 ) alternated biweekly with the same 5-FU/LV regimen plus irinotecan (180 mg/m 2 ). Treatment was maintained until tumor progression or unacceptable toxicity was noted. Results: Median age was 62 years. Performance status was 0/1 in 91% of patients, 63% had 1 organ involved, and 80% had liver metastases.A median of 6 courses per patient (range, 1-9) and a total of 952 infusions were given.The most frequent grade 3/4 toxic events were neutropenia (32%), diarrhea (26%), and asthenia (7%). Grade 1/2 neurotoxicity was seen in 59% of cases, but no grade 3/4 neurotoxicity was observed.There were no toxic deaths. An objective response rate of 54% (4 complete responses plus 39 partial responses) was attained. Median time to progression and overall survival were 13 months and 18 months, respectively. Conclusion: This alternating schedule is active, with efficacy results similar to those seen with sequential protocols, the advantages of less toxicity, and 100% patient exposure to irinotecan and oxaliplatin.

The purpose of this phase II trial was to compare the efficacy, safety and pharmacokinetics of four irinotecan schedules for the treatment of metastatic colorectal cancer. In total, 174 5-fluorouracil pretreated patients were randomised to: arm A (n=41), 350 mg m(-2) irinotecan as a 90-min i.v. infusion q3 weeks; arm B (n=38), 125 mg m(-2) irinotecan as a 90-min i.v. infusion weekly x 4 weeks q6 weeks; arm C (n=46), 250 mg m(-2) irinotecan as a 90-min i.v. infusion q2 weeks; or arm D (n=49), 10 mg m(-2) day(-1) irinotecan as a 14-day continuous infusion q3 weeks. No significant differences in efficacy across the four arms were observed, although a shorter time to treatment failure was noted for arm D (1.7 months; P=0.02). Overall response rates were in the range 5-11%. Secondary end points included median survival (6.4-9.4 months), and time to progression (2.7-3.8 months) and treatment failure (1.7-3.2 months). Similarly, there were no significant differences in the incidence of gra...

Purpose We conducted a phase I/II clinical trial to determine the safety and feasibility of combining vorinostat with 5-fluorouracil (5-FU) in patients with metastatic colorectal cancer (mCRC) and elevated intratumoral thymidylate synthase (TS). Methods Patients with mCRC who had failed all standard therapeutic options were eligible. Intratumoral TS mRNA expression and peripheral blood mononuclear cell (PBMC) histone acetylation were measured before and after 6 consecutive days of vorinostat treatment at 400 mg PO daily. 5-FU/LV were given on days 6 and 7 and repeated every 2 weeks, along with continuous daily vorinostat. Dose escalation occurred in cohorts of three to six patients. Results Ten patients were enrolled. Three dose levels were explored in the phase I portion of the study. Two dose-limiting toxicities (DLTs) were observed at the starting dose level, which resulted in dose de-escalation to levels-1 and-2. Given the occurrence of two DLTs at each of the dose levels, we were unable to establish a maximum tolerated dose (MTD). Two patients achieved significant disease stabilization for 4 and 6 months. Grade 3 and 4 toxicities included fatigue, thrombocytopenia and mucositis. Intratumoral TS downregulation C50% was observed in one patient only. Acetylation of histone 3 was observed in PBMCs following vorinostat treatment. Conclusions The study failed to establish a MTD and was terminated. The presence of PBMC histone acetylation indicates biological activity of vorinostat, however, consistent reductions in intratumoral TS mRNA were not observed. Alternate vorinostat dose-scheduling may alleviate the toxicity and achieve optimal TS downregulation.

We evaluated quantitative measurement series (MS) with 18F-FDG and PET and compared different quantification methods for prediction of individual survival in patients with metastatic colorectal cancer receiving chemotherapy with 5-fluorouracil, folinic acid, and oxaliplatin (FOLFOX). Methods: The study comprised 25 patients. All patients were examined before the onset of FOLFOX therapy and after completion of the first and fourth cycles. SUV, fractal dimension (FD), a 2-compartment model with computation of k1, k2, k3, and k4, and vascular fraction (VB) were used for data evaluation. Survival data served as a reference for the PET data. Discriminant analysis (DA), regression, and best-subset analysis were applied to the data. Results: Twenty of 25 patients died up to 801 d after the first PET study. A cutoff of 1 y (364 d) was used to classify the patients into 2 a priori groups, namely the short- and long-term survival groups. DA was used to predict the 2 categories using SUV and k...

ATP-binding cassette, sub-family C, number 2 (ABCC2) is involved in the biliary excretion of irinotecan and its metabolites, SN-38 and SN-38 glucuronide. Effects of the ABCC2 genotype on the pharmacokinetics (PK) of irinotecan and the metabolites were examined in Japanese patients with metastatic colorectal cancer receiving irinotecan plus infusional 5-fluorouracil/leucovorin (FOLFIRI). ABCC2 genotypes (؊1549GϾA, ؊1023GϾA, ؊1019AϾG, ؊24CϾT, 1249GϾA and 3972CϾT) and haplotypes were analyzed for 67 patients with cancer. PK was also examined in a subset of 31 patients receiving FOLFIRI.

Background Following the discovery that mutant KRAS is associated with resistance to anti-epidermal growth factor receptor (EGFR) antibodies, the tumours of patients with metastatic colorectal cancer are now profi led for seven KRAS mutations before receiving cetuximab or panitumumab. However, most patients with KRAS wild-type tumours still do not respond. We studied the eff ect of other downstream mutations on the effi cacy of cetuximab in, to our knowledge, the largest cohort to date of patients with chemotherapy-refractory metastatic colorectal cancer treated with cetuximab plus chemotherapy in the pre-KRAS selection era.

This report constitutes a prospectively planned meta-analysis combining two almost identical trials undertaken in Australasia and Canada to study the effect of starting chemotherapy immediately in asymptomatic patients with metastatic colorectal cancer. Patients (n=168) were randomised to receive either immediate or delayed treatment (at onset of predefined symptoms). Australasian patients received either weekly 5-fluorouracil and leucovorin (500 and 20mgm−2, respectively) (n=59) or the daily × 5 Mayo Clinic schedule (425 and 20mgm−2, respectively) (n=42). Canadian patients were treated with the Mayo schedule (n=67). Otherwise, the two studies were almost identical in design and each used the European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 instrument for measuring quality of life (QoL). Treatment was continued until 6 months had elapsed or disease progression occurred. Low accrual led to trial suspension before the predetermined sample size for either study was reached. Median survival was not significantly better with immediate treatment (median 13.0 vs 11.0 months; hazard ratio, 1.15; 95% confidence interval (CI) 0.79–1.72; P=0.49). There was no statistically significant difference in progression-free survival (time from randomisation until first evidence of progression after chemotherapy, 10.2 vs 10.8 months; hazard ratio, 1.08; 95% CI 0.71–1.64; P=0.73). There was no difference in overall QoL or its individual domains between the two treatment strategies at baseline or at any subsequent time point. Early treatment of asymptomatic patients with metastatic colorectal cancer did not provide a survival benefit or improved QoL compared to withholding treatment until symptoms occurred.

Metastases are frequently found during colorectal cancer diagnoses and are the main determinants of clinical outcome. The lack of reliable models of metastases has precluded their mechanistic understanding and our capacity to improve outcome. We studied the effect of E-cadherin and Snail1 expression on metastagenesis in a colorectal cancer model. We microinjected SW480-ADH human colorectal cancer cells, transfected with an empty vector (Mock) or overexpressing Snail1 (Snail1 OE ) or E-cadherin (E-cadherin OE ), in the ceca of nude mice (eight per group) and analyzed tumor growth, dissemination, and Snail1, E-cadherin, ␤-catenin, and Presenilin1 (PS1) expression in local tumors and/or metastatic foci. Snail1 OE cells disseminated only to lymph nodes, whereas Mock or E-cadherin OE cells spread to lymph nodes and peritoneums. Peritoneal tumor foci developed by E-cadherin OE cells presented an increase in E-cadherin proteolysis and nuclear translocation, and enhanced expression of proteolytically active PS1, which was linked to increased tumor growth and shortened mouse survival. Interestingly, local and lymph node tumors in mice bearing E-cadherin OE cells overexpressed E-cadherin , but they did not show Ecadherin proteolysis or nuclear translocation. Remarkably , E-cadherin nuclear translocation and enhanced expression of active PS1 were found in a patient with colorectal signet-ring cell carcinoma.

Purpose: Fibroblast Activation Protein (FAP) is a tumor fibroblast protease that has been shown to potentiate colorectal cancer growth. The clinical impact of FAP inhibition was tested using Val-boroPro (Talabostat), the first clinical inhibitor of FAP enzymatic activity, in a phase II study of patients with metastatic colorectal cancer.

In the United States and Europe, colorectal cancer (CRC) is the third most common malignancy and the second leading cause of cancer-related death for men and women. In the course of their disease, many patients will present with metastasis, with the liver and lung being the most common locations. Untreated metastatic disease carries a poor prognosis. However, cure is still possible for selected patients with stage IV CRC. Surgical resection provides the best chance for cure, and chemotherapy can be a valuable adjunct when given in a (neo-)adjuvant fashion or as conversion therapy to downsize initially unresectable tumors. For unresectable metastases, alternative treatment options include radiofrequency ablation and hepatic artery infusion. Additional local therapies are being explored, including chemoembolization, radioembolization, and stereotactic body radiation therapy. Prospective randomized trials are needed to further clarify the roles of these novel treatment options in the clinician's repertoire for metastatic CRC.

BACKGROUND: A dose-finding study was performed to evaluate the dose-limiting toxicity (DLT), maximum-tolerated dose (MTD) and the recommended dose (RD) of escalating the doses of capecitabine and fixed doses of irinotecan and oxaliplatin on a biweekly schedule for metastatic colorectal cancer patients (mCRC). A pharmacogenomic analysis was performed to investigate the association between SNPs and treatment outcome. METHODS: Eighty-seven chemotherapy-naïve mCRC patients were recruited through a two-step study design; 27 were included in the dose-finding study and 60 in the pharmacogenomic analysis. Oxaliplatin (85 mg m -2 ) and CPT-11 (150 mg m -2 ), both on day 1, and capecitabine doses ranging from 850 to 1500 mg m -2 bid on days 1 -7 were explored. Peripheral blood samples were used to genotype 13 SNPs in 10 genes related to drug metabolism or efficacy. Univariate and multivariate Cox analysis was performed to examine associations between SNPs, ORR and PFS. RESULTS: The capecitabine RD was 1000 mg m À2 bid. Diarrhoea and neutropenia were the DLTs. After a median follow-up of 52.5 months, the median PFS and OS were 12 (95% CI; 10.6 -13.4) and 27 months (95% CI; 17.2 -36.8), respectively. The GSTP1-G genotype, the Kö hne low-risk category and use of a consolidation approach strongly correlated with decreased risk of progression. Patients with all favourable variables showed a median PFS of 42 months vs 3.4 months in the group with all adverse factors. A superior clinical response was obtained in patients with one GSTP1-G allele as compared with GSTP1-AA carriers (P ¼ 0.004). CONCLUSION: First-line therapy with oxaliplatin, irinotecan and capecitabine is efficient and well-tolerated. The GSTP1 polymorphism A4G status was significantly associated with ORR and PFS in mCRC treated with this triplet therapy.