Pretreated Advanced Colorectal Cancer Research Articles

454O - A randomized phase III study of napabucasin [BBI608] (NAPA) vs placebo (PBO) in patients (pts) with pretreated advanced colorectal cancer (ACRC): the CCTG/AGITG CO.23 trial

454O - A randomized phase III study of napabucasin [BBI608] (NAPA) vs placebo (PBO) in patients (pts) with pretreated advanced colorectal cancer (ACRC): the CCTG/AGITG CO.23 trial

Regorafenib assessment in refractory advanced colorectal cancer: RegARd-C study protocol

IntroductionRegorafenib was recently approved for patients with pretreated advanced colorectal cancer (aCRC), despite a moderate improvement of the patients’ outcome, and significant toxicities. Based on previous studies showing that early...

Optimizing Single Agent Panitumumab Therapy in Pre-Treated Advanced Colorectal Cancer

PURPOSE: To improve the selection of advanced colorectal cancer patients to panitumumab by optimizing the assessment of RAS (KRAS-NRAS) mutations. EXPERIMENTAL DESIGN: Using a centralized pyrosequencing RAS assay, we analyzed the tumors of 94 patients, wild-type for KRAS mutations (codons 12 to 13) by Sanger sequencing (SS), treated with panitumumab. RESULTS: By SS analysis, 94 (62%) of 152 patients were wild-type and their objective response rate to panitumumab was 17%. We first optimized the KRAS test, by performing an accurate tissue-dissection step followed by pyrosequencing, a more sensitive method, and found further mutations in 12 (12.8%) cases. Secondly, tumors were subjected to RAS extension analysis (KRAS, exons 3 to 4; NRAS exons 2 to 4) by pyrosequencing that allowed to identify several rare mutations: KRAS codon 61, 5.3%; codon 146, 5.3%; NRAS, 9.5%. Overall, RAS mutation rate was 32.9%. All patients with additional RAS mutations had progressive or stable disease, except 3 patients with mutations at codon 61 of KRAS or NRAS who experienced partial (2 cases) or complete response. By excluding from the analysis 11 cases with mutations at codons 61, no patient was responsive to treatment (P=.021). RAS wild-type versus RAS mutated cases had a significantly better time to progression (P=.044), that resulted improved (p=.004) by excluding codon 61 mutations. CONCLUSION: This study shows that by optimizing the RAS test it is possible to significantly improve the identification of patients who do not gain benefit of panitumumab. Prospective studies are warranted to determine the clinical significance of rare mutations.

Regorafenib assessment guided by metabolic imaging in refractory advanced colorectal cancer (aCRC): REGARD-C study.

Background: Regorafenib, an oral multi-tyrosine kinase inhibitor that shares with sorafenib several targets on tumor angiogenesis, oncogenesis, and tumor microenvironment, was recently approved for patients (pts) with pretreated advanced colorectal cancer (aCRC). The drug improves the pts’ outcome, but with significant toxicities, underscoring the need to identify those who will not benefit. A previous study (SoMore trial) showed that early FDGPET-based metabolic response assessment (MRA) may adequately discriminate pts with chemorefractory aCRC unlikely to benefit from a sorafenib-capecitabine combination. RegARd-C aims to explore early MRA in pts treated with regorafenib as a clinical tool to spare pts from needless toxicity from a drug that gives them little or no benefit and as a translational tool to guide comprehensive genomic and epigenetic research on the determinants of drug resistance. Methods: RegARd-C’s (EUDRACT 2012-005655-16) is a multi-centric prospective study. Its primary objective is to identify in a population of pts with pretreated aCRC, those who will not benefit from regorafenib given at 160 mg/day, three weeks/4. Baseline PET is repeated at D14 of the first treatment course. MRA results are blinded for the investigators. Tumor tissues, optionally obtained from a PET-measurable lesion, and blood samples (at baseline; after the first chemotherapy course; and every two months) are collected. Overall survival (OS) is the primary endpoint and will be correlated with metabolic parameters, and genetic, epigenetic and molecular aberrations assessed from tumor biopsies and blood samples using gene expression and methylation profiling, RNA and exome sequencing. As the study is exploratory, no formal hypothesis was formulated. We arbitrarily decided to have a sample size of 105 evaluable pts with 70 pts as a derivation set and 35 pts as a validation set. Taking into account an expected 20-25% drop-out rate, between 124 and 140 pts will be accrued.This sample size is, however, sufficient to validate the hypothesis generated by the SoMore study, which found a prognostic impact of homogeneous metabolic response on OS, with an estimated HR of 0.59. RegARd-C has accrued 76 pts since August 2013. Clinical trial information: NCT01929616.

A phase 1b study of VEGFR inhibitor fruquintinib in patients with pretreated advanced colorectal cancer.

3548 Background: Fruquintinib is a novel oral small molecule compound selectively inhibits vascular endothelial growth factor receptors (VEGFR) 1, 2, and 3 with potent inhibitory effects on multipl...

Role of derived neutrophil lymphocyte ratio as a biomarker in advanced colorectal cancer

BackgroundThe discovery and validation of prognostic and predictive biomarkers in advanced colorectal cancer is crucial for the personalisation of therapy. Inflammation-based prognostic scores have been developed, including the neutrophil lymphocyte ratio (NLR), and the derived NLR (dNLR) calculated using a differential white cell count. The NLR has been assessed in several cancers; in a retrospective series of advanced colorectal cancer, higher NLR was associated with reduced survival and poorer outcomes with chemotherapy. We aimed to validate the usefulness of the dNLR as a prognostic and a predictive biomarker to anti-epidermal growth factor receptor (EGFR) agents in advanced colorectal cancer. MethodsWe studied patients from a phase 3, open-label, randomised controlled trial that assessed the addition of panitumumab to irinotecan in pretreated advanced colorectal cancer (PICCOLO trial). The prognostic analysis included all patients for whom dNLR data were available; a subset with KRAS wild-type tumours randomised to standard irinotecan with or without panitumumab was also analysed for predictive value. The dNLR was calculated from the prerandomisation blood count and categorised as high (≥2) or low (<2). Prognostic and predictive values of the dNLR were assessed with Cox's proportional hazard and logistic regression, adjusting for known prognostic factors in advanced colorectal cancer. Findings1159 patients were included in the prognostic analysis, and 444 in the predictive analysis. In multivariate analysis, high dNLR was independently associated with reduced overall survival compared with low dNLR (hazard ratio 1·59, 95% CI 1·32–1·78; p<0·001), the only other significant factor being poor performance status (p<0·001). High dNLR was also associated with reduced progression free survival (1·29, 1·13–1·47, p<0·001). In the predictive analysis, dNLR was not predictive of overall benefit with the addition of panitumumab to irinotecan. The main trial results showed that the benefit of panitumumab is confined to patients with no mutations in EGFR downstream pathways (KRAS, BRAF, NRAS, and PIK3CA), and in the subset of 323 patients in this all-wild-type category panitumumab had a more marked effect on tumour response rate in patients with low dNLR (odds ratio 7·4, p<0·001) than in those with high dNLR (3·7, p<0·001); however, interaction testing was not significant. InterpretationThe dNLR seems to offer the clinician useful prognostic information. Since this information can easily be calculated from routine clinical data, its integration into routine patient assessment should be considered after further validation. We did not demonstrate significant predictive value for anti-EGFR therapy, but our finding of higher response with panitumumab in patients with a low dNLR is hypothesis generating. Further investigation in datasets from randomised controlled trials and exploratory translational work are warranted. FundingCancer Research UK, Yorkshire Cancer Research.

Association of hypomagnesemia with inferior survival in a phase III, randomized study of cetuximab plus best supportive care versus best supportive care alone: NCIC CTG/AGITG CO.17

BackgroundCetuximab-induced hypomagnesemia has been associated with improved clinical outcomes in advanced colorectal cancer (CRC). We explored this relationship from a randomized clinical trial of cetuximab plus best supportive care (BSC) versus BSC alone in patients with pretreated advanced CRC. Patients and methodsDay 28 hypomagnesemia grade (0 versus ≥1) and percent reduction (<20% versus ≥20%) of Mg from baseline was correlated with outcome. ResultsThe median percentage Mg reduction at day 28 was 10% (-42.4% to 63.0%) for cetuximab (N = 260) versus 0% (-21.1% to 25%) for BSC (N = 251) [P < 0.0001]. Grade ≥1 hypomagnesemia and ≥20% reduction from baseline at day 28 were associated with worse overall survival (OS) [hazard ratio, HR 1.61 (95% CI 1.12–2.33), P = 0.01 and 2.08 (95% CI 1.32–3.29), P = 0.002, respectively] in multivariate analysis including grade of rash (0–1 versus 2+). Dyspnea (grade ≥3) was more common in patients with ≥20% versus < 20% Mg reduction (68% versus 45%; P = 0.02) and grade 3/4 anorexia were higher in patients with grade ≥1 hypomagnesemia (81% versus 63%; P = 0.02). ConclusionsIn contrast to prior reports, cetuximab-induced hypomagnesemia was associated with poor OS, even after adjustment for grade of rash.

The influence of hypomagnesemia (hMg) on overall survival (OS) in a phase III randomized study of cetuximab (CET) plus best supportive care (BSC) versus BSC: NCIC CTG/AGITG CO.17.

3601 Background: CET-induced hMg was reported as an early predictor of improved clinical outcomes in advanced colorectal cancer (ACC) [Vincenzi, 2010]. We explored this relationship in a prior clinical trial of CET plus BSC versus BSC in patients with pretreated ACC, in which magnesium (Mg) was prospectively collected at baseline and monthly. Methods: End of month 1 (EM1) hMg grade and percent reduction (≥20% vs <20%) of Mg from baseline was correlated with patient characteristics and outcomes (by landmark analysis). Results: The baseline median Mg was 0.83 (range 0.33-1.29) and 0.83 mmol/L (range 0.55-1.05) for patients on CET (N=260) and BSC (N=251) respectively, and decreased to 0.77 mmol/L (0.27-1.04) and 0.82 (0.51-1.06) respectively at EM1. The median % Mg reduction at EM1 was respectively 10% (-42.4 to 63.0%) for patients on CET and 0% (-21.1 to 25%) on BSC [p<0.0001]. Mg reduction ≥20% occurred in 32 (15.6%) patients on CET and 1 (0.7%) on BSC [p<0.0001]. The OS by Mg grade and reduction from baseline for CET patients are shown in the table. Grade ≥1 hMg or ≥20% reduction from baseline at EM1 was associated with worse OS (aHR 1.61; 95% CI 1.12 - 2.33, p=0.01 and 2.08; 95% CI 1.32 - 3.29, p=0.002, respectively) in multivariate analysis including grade of rash (0 or 1 v 2+). Dyspnea was higher in patients with ≥20% Mg reduction (68% vs. 45%; p=0.02). Dose intensity did not differ based on grade or % reduction of Mg. Quality of life data will be presented. Conclusions: In contrast to prior reports, grade ≥1 (and ≥20% reduction from baseline) CET-induced hMg was associated with poor OS, even after adjustment for grade of rash. Mg Median OS Adjusted HR (aHR) N Months 95% CI HR 95% CI p All Grade 0 163 8.0 6.6-9.8 0.63 0.43-0.91 0.01 >0 53 3.7 3.0-5.0 Reduction <20% 172 7.6 6.4-9.5 0.50 0.32-0.78 0.003 ≥20% 31 3.8 2.7-4.9 Wild type KRAS Grade 0 73 9.9 8.3-11.6 0.45 0.22-0.91 0.03 >0 17 4.4 2.3-9.8 Reduction <20% 75 9.8 8.0-10.9 0.43 0.18-1.04 0.06 ≥20% 9 6.5 5.0-9.8 Mutated KRAS Grade 0 45 5.6 4.8-8.2 0.44 0.22-0.91 0.03 >0 17 3.5 2.1-5.5 Reduction <20% 49 5.9 4.2-8.2 0.53 0.21-1.35 0.18 ≥20% 10 3.3 2.0-4.8

Dose finding study of erlotinib combined to capecitabine and irinotecan in pretreated advanced colorectal cancer patients

This study evaluated the maximum tolerated dose (MTD) and the dose limiting toxicity (DLT) of erlotinib when combined to irinotecan and capecitabine in pre-treated metastatic colorectal cancer patients. Five dose level combinations with irinotecan (from 180 to 240 mg/m(2), day 1, q21), capecitabine (1,500-2,000 mg/m(2) per day, days 2-15, q21) and erlotinib (50-150 mg per day, continuously) were planned. Patients were enrolled in cohorts of three, and evaluated for first cycle acute toxicity. Twenty-one patients were treated. In the first cohort, no DLT was reported, in the second: one DLT (G4 neutropenic fever associated with G3 cutaneous rash and mucositis); in the third dose level: two DLT (G3 diarrhea and G4 neutropenic fever). To confirm these results, other six patients were additionally included and no DLT was observed. The results documented that erlotinib at the dose of 100 mg per day, irinotecan 180 mg/m(2) and capecitabine 1,500 mg/m(2) per day for 14 days has an acceptable safety profile and appears suitable for further phase II studies.

Quality of life in patients with advanced colorectal cancer treated with cetuximab: Results of the NCIC CTG and AGITG CO.17 trial

4002 Background: Cetuximab prolongs survival in pretreated advanced colorectal cancer (CRC) patients (pts). For these pts, the effect of palliative treatment on quality of life (QOL) is also an important outcome. Methods: CO.17 was a randomized controlled trial (n=572) of cetuximab combined with best supportive care (BSC) vs BSC alone in pts with pretreated epidermal growth factor receptor-positive advanced CRC. Primary endpoint was survival. QOL was a secondary endpoint using the EORTC QLQ-C30 at baseline, 4, 8, 16, and 24 weeks (wks). Primary endpoint for QOL compared physical function (PF) and global health status (Global) mean changes from baseline to 8 and 16 wks using Wilcoxon test. Negative change scores denote worsening QOL. The proportion of pts in either arm with at least a 10 unit deterioration at 8 and 16 wks from baseline was compared using Fischer’s exact test. Kaplan-Meier estimates and logrank tests on median time to definitive QOL deterioration, defined as at least a 10 unit deterioration in PF or Global, were evaluated. Exploratory analyses of all other scale and symptom change scores at 8 and 16 wks were also performed. Results: Compliance rates for QOL questionnaires was high at baseline, 94% each arm, but did drop off over time: 73% vs 60% at week 8 and 60% vs 39% at week 16 for cetuximab vs BSC, respectively. PF change scores at 8 wks were -3.9 for cetuximab vs -8.6 for BSC (p=.046); at 16 wks -5.9 vs -12.5 (p=.027). Global change scores were -0.5 vs -7.1 (p=.008) and -3.6 vs -15.2 (p=.008) at 8 and 16 wks respectively. The proportion of pts with deteriorating PF was 25% for cetuximab vs 35% for BSC at 8 wks (p=.051) and 30 vs 43% at 16 wks (p=.069). Deteriorating Global was seen in 23 vs 38% at 8 wks (p=.004) and 31 vs 49% at 16 wks (p=.0011). Time to PF deterioration was 5.4 months [95% CI 3.8–5.7] for cetuximab vs 3.7 months [2.0–3.9] for BSC (p=.022). Time to Global deterioration was 5.4 [3.9–5.7] vs 3.7 months [2.1–3.9] (p=.062). Exploratory analyses of all other scale and symptom change scores at 8 and 16 wks showed all differences of p&lt;.05 also favored cetuximab. Conclusions: Cetuximab provides palliation in pretreated pts with advanced CRC, delaying deterioration in QOL as well as improving survival. [Table: see text]

Circulating VEGF Reduction, Response and Outcome in Advanced Colorectal Cancer Patients Treated with Cetuximab Plus Irinotecan

We designed this trial to investigate if modifications in levels of circulating vascular endothelial growth factor (VEGF) may be related to clinical response and outcome in advanced colorectal cancer patients during treatment with a weekly combination of cetuximab plus irinotecan. A total of 45 heavily pretreated metastatic colorectal cancer patients were prospectively evaluated for circulating levels of VEGF during the treatment with cetuximab plus weekly irinotecan. VEGF circulating levels were assessed at the following time points: just before and at 1, 21, 50 and 92 days after the start of cetuximab plus irinotecan treatment. Basal VEGF median levels were significantly decreased just 1 day after the first anticancer infusion (p = 0.016) and reached the highest statistical significance 92 days after the first infusion (p < 0.0001). A total of 22 patients showed a reduction in median VEGF circulating levels of at least 50% 92 days after the first infusion with respect to the basal time point. For patients with at least a 50% reduction in VEGF levels, the response rate was 45.5% compared with 8.7% in the nonreduced VEGF group (p = 0.014). The median time to progression was 6 months in the reduced VEGF group versus 3.9 months in the other patients (p < 0.0001). In addition, overall survival was longer in patients with VEGF reduction (11.0 months) than in patients without (9.6 months; p = 0.01). These data represent the first evidence that suggests a role of VEGF reduction in the prediction of efficacy of treatment with cetuximab plus weekly irinotecan in heavily pretreated advanced colorectal cancer patients.

Chemotherapy with Mitomycin C and Capecitabine in Patients with Advanced Colorectal Cancer Pretreated with Irinotecan and Oxaliplatin

To assess the activity and tolerability of the combination of mitomycin C and capecitabine in patients with metastatic colorectal cancer after failure of irinotecan and oxaliplatin-containing regimens. We retrospectively reviewed 28 patients with pretreated advanced colorectal cancer who had been treated with mitomycin C, 6 mg/m2 on day 1, and capecitabine, 1900 mg/m2 on days 1-14, every 3 weeks. Tumor assessment was performed every 3 cycles, toxicity assessed at each cycle. Main patient characteristics were median age, 61 years (range, 35-73); male/female ratio, 16/12; single metastatic site involvement, 5/28 (18%); > or =3 metastatic sites, 10/28 (36%). Ninety-six courses of therapy were given (median number, 3; range, 1-9). Twenty-six patients were assessable for response, and all were assessable for toxicity. There was 1 partial response (4%) and 12 had stable disease (43%). Median time to progression was 2 months (range, 1-9) and median overall survival was 6 months (range, 1-29+), with a 1-year overall survival rate of 25%. The regimen was very well tolerated without significant hematological toxicity. Our results are disappointing. Despite the good safety profile, they do not support further investigation or the routine use of this regimen in this setting.

Phase II study of fixed dose rate gemcitabine in patients with pretreated advanced colorectal cancer

13558 Background: There is preclinical evidence that gemcitabine has activity in colon cancer. However, previous clinical studies have not clearly demonstrated activity of gemcitabine given as a 30 minute infusion. Prolonged exposure of colon cancer cell lines to gemcitabine appears to have greater antitumour effect compared to shorter exposure (Kornmann et al, Eur J Surg Oncol 2000). Methods: Patients with progressive, pretreated metastatic colorectal cancer received gemcitabine 1500 mg/m2 at a fixed dose rate of 10 mg/m2/min (150 minutes) D1, 8, 15 every 28 days. The primary endpoint was disease control rate (CR/PR/SD) assessed by CT scan. Using a 2-stage statistical design, a total of 37 patients were required to demonstrate at least a 25% disease control rate with 90% power and a 1-sided alpha of 0.05. The 1st accrual stage required at least 6/17 pts to obtain disease control, prior to proceeding to the 2nd stage. Results: 16 patients with a median age of 63 years were treated. The median number of prior lines of chemotherapy was 3 (range: 1–5). The median number of administered gemcitabine doses was 5.5 (range: 1–14). 3 patients achieved SD after 3 cycles, but subsequently progressed. 13 patients either progressed prior to the first scheduled CT scan or had declining performance status requiring removal from the study. 1 patient experienced transient reduction in serum CEA of &gt; 50%. Median progression-free survival was 77 days (95% CI 61–93). Grade 3/4 neutropenia occurred in 4/1 pts; grade 3/4 thrombocytopenia in 6/0 pts. 2 pts had grade 3 infection. As only 3/16 pts achieved disease control, it was not possible to proceed to the 2nd stage and the study was closed to accrual. Conclusions: Gemcitabine administered by fixed dose rate infusion has minimal activity in heavily pretreated patients with advanced colorectal cancer. Gemcitabine monotherapy is not recommended in this patient population. No significant financial relationships to disclose.

Angiogenesis modifications are predictive of response and outcome in heavily pretreated advanced colorectal cancer patients during therapy with cetuximab plus irinotecan

3562 Background: Angiogenesis has been correlated with increased invasion and metastases in a variety of human neoplasms. Inadequate inhibition of the growth of tumor microvessels by anticancer agents may result in treatment failure, rated clinically as progressive or stable disease. We designed this trial to investigate if Vascular Endothelial Growth Factor (VEGF) circulating levels modifications may be related with clinical response and outcome in advanced colorectal cancer patients during treatment with a weekly combination of cetuximab plus irinotecan. Methods: 45 heavily pretreated metastatic colorectal cancer patients were prospectively evaluated for circulating levels of VEGF during the treatment with cetuximab (initial dose of 400 mg per square meter, followed by weekly infusions of 250 mg per square meter) plus weekly irinotecan (90 mg per square meter). VEGF circulating levels were assessed at the following time-points: just before and at 1, 21, 50 and 92 days after the start of cetuximab plus irinotecan treatment. Results: Basal serum VEGF median levels were significantly decreased just at the first day (after the first treatment infusion (P=0.016). The VEGF persisted at the following time points reaching the highest statistical significance 92 days after the first infusion (P&lt;0.0001). Twenty-two patients showed a reduction in median VEGF circulating levels of at least 50% 92 days after the first infusion respect to the basal time point. In the group of patients with at least 50% reduction of VEGF levels the response rate was 59.1% vs 21.7% in the non reduced VEGF group (P=0.024). Moreover, the median time to progression was 6.12 months (95% C.I.: 3.9 - 7.1) in the reduced VEGF group vs 2.3 months (95% C.I.: 1.6 - 3.5) in the other patients (P=0.001). Finally, also overall survival was longer in patients who developed VEGF reduction (12.3 months; 95% C.I.: 8.65 - 15.9) than this recorded in patients without the reduction (6.4 months; 95% C.I.: 5.6 - 8.4) (P=0.05). Conclusions: The present data represent the first evidence that suggest a role of VEGF reduction in the prediction of efficacy of treatment with cetuximab plus weekly irinotecan in heavily pretreated advanced colorectal cancer patients. No significant financial relationships to disclose.

Phase II randomized trial on protracted 5-fluorouracil infusion plus oxaliplatin (FOX) versus capecitabine plus oxaliplatin (XELOX) as first-line treatment in advanced colorectal cancer (ACRC): Preliminary results of the Italian FOCA Study

3617 Background: FOX regimen has shown to be safe and active in pretreated ACRC pts. Capecitabine (CAPE), an oral fluoropyrimidine, has been explored as an alternative to infusional 5-fluorouracil (5FU) in oxaliplatin (OXA) containing regimen (XELOX). The aim of this phase II randomized trial was to compare the efficacy and safety of FOX and XELOX as first line therapy in ACRC pts. Methods: From December 2001 to December 2004, 100 eligible untreated pts with ACRC have been randomized to arm A (FOX) (5-fluorouracil protracted infusion iv 250 mg/m2 d1–21 + oxaliplatin 130 mg/m2 iv d1, q3w) or arm B (XELOX) (capecitabine 1000 mg/m2 po bid d1–14, q3w + oxaliplatin 130 mg/m2 iv d1,q3w). Fourty-eight pts were randomized to arm A and 52 to arm B. Results: Baseline pt characteristics were well balanced between the two arms: M/F 52/48, median age 66.8 years (41–79); median KPS 90 (70–100); colon 71%, rectum 29%; primary tumor resection 80.9%; adjuvant chemotherapy 24%; metastatic sites: liver 77% (only liver 43%), lung 35%, lymph nodes 21%. Median number cycles was: 5 (1–10) in arm A and 6 (1–10) in arm B. Median dose intensity was: 5FU 100% (13–100) and OXA 100% (82–100) in arm A; CAPE 100% (16–100) and OXA 100% (60–100) in arm B. At the moment 75 pts were evaluable for response and 93 pts for toxicity. The objective responses were: arm A CR 3%, PR 48.5%, SD 27.3%, PD 21.2%; arm B CR 7.1%, PR 38.1%, SD 33.3%, PD 21.4%; RR 51.5% vs 45.2%. In arm A and B median TTP was 6 vs 9 months. Survival data are immature (58% of pts are still alive). Surgical resection of liver metastases after chemotherapy was performed in 4.1% pts in arm A vs 9.6% pts in arm B. Only 1 pt showed grade 4 toxicity (NCI-CTC2) (diarrhea) in arm A. Grade 3 treatment-related toxicity in arm A and B was: neutropenia 2.4% vs 0; thrombocytopenia 2.4% vs 2.4%; stomatitis 4.8% vs 0; diarrhea 14.3% vs 3.9%; hypertransaminasemia 0 vs 2%; hyperbilirubinemia 2.3% vs 2.1%; neurotoxicity 15.0% vs 20.4%. Conclusions: Our preliminary results suggest that FOX and XELOX, as administered in this trial, show high activity as first line treatment. Toxicity is low and similar in the two arms. No significant financial relationships to disclose.

Gemcitabine plus continuous infusion of 5-FU for heavily pretreated advanced colorectal cancer patients. Phase I/II study

3735 Background: Colorectal cancer (CRC) patients previously treated with more than one regimen but still with good performance status are a frequent clinical reality. It is necessary to investigat...

Oral fluoropirimidine treatment of heavily pretreated advanced colorectal cancer patients

Oral fluoropirimidine treatment of heavily pretreated advanced colorectal cancer patients

Oxaliplatin Added to Simplified Bimonthly Low-Dose Leucovorin and 5-FU for Pretreated Advanced Colorectal Cancer Is Effective and Not Affected by Different Previous 5-FU Regimens

This phase II study examined bimonthly oxaliplatin (85 mg/m2) added to a continuous infusion of fluorouracil (3000 mg/m2 for 46 h following a 400 mg/m2 bolus), with leucovorin (LV) (150 mg/m2) administrated in a simplified way to patients with metastatic colorectal cancers (CRC) refractory or resistant to 5-fluorouracil (5-FU). Sixty patients were registered. Of the 52 evaluable patients, 3 (5.8%) achieved a complete response (CR) and 18 (34.6%) achieved a partial response (PR). The overall response rate (CR + PR) was 40.4% (95% confidence interval [CI]: 26.6%–54.2%) for evaluable patients and 35% (95% CI: 22.6%–47.4%) by intention to treat. The median progression-free survival (PFS) was 5.2 months, and the median survival was 14.2 months. No significant differences were seen in response rates and PFS of patient groups pretreated either with high-dose 5-FU/LV by continuous infusion or with intravenous 5-FU/LV by a weekly bolus. From the 421 cycles analyzed, dose-limiting toxicities included cumulative sensory neuropathy and leukopenia, accounting for 11.6% and 10.0%, National Cancer Institute–Common Toxicity Criteria grade 3/4 toxicities per patient, respectively. Two (3.3%) patients experienced hepatic encephalopathy related to high-dose 5-FU. With necessary caution, this regimen was effective for 5-FU-pretreated CRC, regardless of ethnic differences, and it had the advantage of LV being administrated at a low dose in a simplified way.

Oxaliplatin with Weekly Bolus 5-Fluorouracil and Leucovorin in Pretreated Advanced Colorectal Cancer Patients: A Phase II Study

Background: The purpose of this study was to determine the efficacy and toxicity of oxaliplatin in combination with weekly bolus 5-fluorouracil (5-FU) and leucovorin (LV) in patients with 5-FU-pretreated advanced colorectal cancer. Methods: A total of 39 patients with documented 5-FU-resistant advanced colorectal cancer were enrolled. All 39 patients had previously received weekly high-dose 5-FU/LV (2,600 mg/m² 5-FU plus 100 mg/m² LV as 24-hour infusion) as first-line chemotherapy for metastatic disease. Oxaliplatin (85 mg/m²) was delivered as an intravenous infusion over 2 h on days 1 and 15, while 5-FU (500 mg/m²) and LV (20 mg/m²) were administered as an intravenous bolus on days 1, 8 and 15. One treatment course consisted of 3 consecutive weeks of therapy followed by a 1-week rest. Results: In an intent-to-treat analysis, the objective response rate for the 39 patients was 20.5% (95% confidence interval, 7.2–33.8%). The disease was stable in 19 patients (48.7%), and progressive in 11 (28.2%). The median survival for all 39 patients was 8.9 months. The median time to progression was 5.0 months. Grade 3/4 neutropenia occurred in only 1 patient (2.6%), and grade 2 and 3/4 peripheral neuropathy occurred in 10 (25.6%) and 5 (12.8%) patients, respectively. Conclusion: Oxaliplatin in combination with weekly bolus 5-FU/LV is also active in patients with advanced colorectal cancer where first-line treatment has failed.

A Phase II Study of Oxaliplatin Combined with 5-Fluorouracil and Leucovorin (Mayo Clinic Regimen) in 5-Fluorouracil Refractory Colorectal Cancer.

There are few therapeutic options in patients with colorectal cancer that have progressed or recurred following 5-fluorouracil (5-FU) based therapy. We evaluated the efficacy and toxicity of oxaliplatin, 5-FU, leucovorin (Mayo clinic regimen) in 5-FU pretreated advanced colorectal cancer patients. MATERIALS AND METGODS: Twenty-eight patients were enrolled in this study between January 1999 and May 2001. Patients were treated with oxaliplatin 150 mg/m2 on day 1 as a 2-hr infusion and 5-FU 425 mg/m2, leucovorin 20 mg/m2, bolus for 5 days. Treatment courses were repeated in 4-week intervals. The objective response rate was 25% for 28 assessable patients, all cases registered a partial response. Eleven patients (39%) demonstrated stable disease, and ten (36%) progressed. The median response duration was 5.5 months, and the median time to progression was 6.3 months. The median overall survival time was 13.5 months from the start of the chemotherapy. From the 120 cycles analyzed, grade 3,4 hematologic toxicities included neutropenia: 1.6%, and thrombocytopenia: 1.6%. The frequent grade 3.4 non-hematologic adverse reactions were nausea/vomiting (25.0%), diarrhea (14.3%), stomititis (3.6%), and neuropathy (3.6%). There were no treatment-related deaths. This phase II study had relatively higher toxicity than previous studies, and did not show an increased significant response rate. These high levels of toxicity suggest that the study treatment combination of oxaliplatin with a full dose Mayo clinic regimen arm is no feasible. Therefore, this regimen will be discontinued and a safer regimen will be adopted.