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Background: Patients with unresectable recurrent rectal cancer (RRC) or colorectal cancer (CRC) with liver metastases, refractory to at least two lines of traditional systemic therapy, may receive third line intraarterial chemotherapy (IC) and targeted therapy (TT) using drugs selected by chemosensitivity and tumor gene expression analyses of liquid biopsy-derived circulating tumor cells (CTCs)., Methods: In this retrospective study, 36 patients with refractory unresectable RRC or refractory unresectable CRC liver metastases were submitted for IC and TT with agents selected by precision oncotherapy chemosensitivity assays performed on liquid biopsy-derived CTCs, transiently cultured in vitro, and by tumor gene expression in the same CTC population, as a ratio to tumor gene expression in peripheral mononuclear blood cells (PMBCs) from the same individual. The endpoint was to evaluate the predictive accuracy of a specific liquid biopsy precision oncotherapy CTC purification and in vitro culture methodology for a positive RECIST 1.1 response to the therapy selected., Results: Our analyses resulted in evaluations of 94.12% (95% CI 0.71-0.99) for sensitivity, 5.26% (95% CI 0.01-0.26) for specificity, a predictive value of 47.06% (95% CI 0.29-0.65) for a positive response, a predictive value of 50% (95% CI 0.01-0.98) for a negative response, with an overall calculated predictive accuracy of 47.22% (95% CI 0.30-0.64)., Conclusions: This is the first reported estimation of predictive accuracy derived from combining chemosensitivity and tumor gene expression analyses on liquid biopsy-derived CTCs, transiently cultured in vitro which, despite limitations, represents a baseline and benchmark which we envisage will be improve upon by methodological and technological advances and future clinical trials., (© 2022. The Author(s).)

Background: Hepatic artery infusion (HAI) and drug selection by liquid biopsy precision oncotherapy are under investigation for the multidisciplinary treatment of unresectable colorectal liver metastases (CRCLM) in progression after systemic therapy. Here, we compare the safety and efficacy of third-line HAI followed by target therapy with drug regimes selected by liquid biopsy precision oncotherapy to third-line systemic therapy with drug regimes selected partly by tissue biopsy precision oncotherapy, in a retrospective real-life study of 106 unresectable CRCLM patients., Methods: Drug regimens for HAI/target therapy were selected by assessing the sensitivity of purified circulating tumor cell (CTCs) to 5-fluorouracil, carboplatin, cisplatin, oxaliplatin, irinotecan, doxorubicin, mitomycin, raltitrexed, and melphalan in-vitro and by real-time qRT-PCR gene expression assays, and for the Systemic therapy cohort were selected by age, comorbidity, performance status, and absence of RAS mutations. Therapeutic responses, adverse events, and quality of life were evaluated by RECIST 1.1, CTCAE 4.03, and ECOG criteria, respectively, and chemo-filtration performed following HAI to reduce systemic toxic effects., Results: HAI/target therapy with drugs selected by liquid biopsy precision oncotherapy (44 patients), resulted in 2.27% CRs, 38.63% PRs, 56.81% SD,s and 2.27% PDs; ECOG 2 to 1 improvement, but no infusion-related technical or vascular complications, or deaths. Systemic therapy (62 patients) resulted in 1.6% CRs, 17.74% PRs, 37.09% SDs, and 45.16% PDs; more grade 1-2 adverse events and 4.84% ECOG 1 to 2 worsening. The median 5 month PFS in the HAI/target therapy cohort was significantly longer than 3 months in the systemic cohort (P < 0.007) and the median 14 month survival in the HAI/target therapy cohort was longer than 8.5 months in the systemic therapy cohort but not statistically significant. Multivariate analysis identified ECOG grade 2 as the most unfavourable survival prognostic factor in both cohorts., Conclusions: HAI plus chemo-filtration followed by target therapy, with drug regimens selected by liquid biopsy precision oncotherapy, is a safe and efficacious alternative therapeutic strategy for unresectable CRCLM in progression after two lines of systemic therapy and should be considered for a multicentre prospective phase III study, to fully confirm this potential.

We describe a metastatic colorectal cancer patient, treated with first-line 5-fluorouracil, irinotecan, bevacizumab, and oxaliplatin (FIr-BFOx) therapy, with aggressive and resistant disease. KRAS, NRAS, BRAF, and PI3KCA were analyzed in primary tumor and liver metastasis. KRAS c.34G>A mutation was detected in primary tumor and liver metastasis, which additionally revealed 2 rare PI3KCA mutations (c.1633G>C and c.1645G>C). The c.1645G>C was never reported in colorectal cancer. Akt/p-Akt Ser473 , phosphatase and tensin homolog, mismatch repair, and epidermal growth factor receptor expression was evaluated. Normal mismatch repair and epidermal growth factor receptor expression was detected. Akt was shown by primary tumor and liver metastasis, whereas p-Akt Ser473 was identified only in the latter, despite positive phosphatase and tensin homolog expression. Patient showed 7 months of progression-free survival and 15 months of overall survival, lower than median values reported in KRAS exon 2-mutant patients treated with the same therapy. Results lead to the hypothesis of a putative role of these mutations in worsening of the disease and are open to further confirmatory studies., (Copyright © 2018. Published by Elsevier Inc.)

Introduction: Bevacizumab addiction to triplet chemotherapy, according to FIr-B/FOx schedule, as first-line treatment in young-elderly metastatic colorectal CANCER (MCRC) patients may be more effective. Tailored treatments show worse clinical outcome in unfit patients., Methods: Elderly patients were clinically evaluated according to age and comorbidity (Cumulative Illness Rating Scale) to select FIr-B/FOx regimen in fit or tailored treatments in unfit elderly. Limiting toxicity syndromes (LTS) were evaluated., Results: At 17 months follow-up, in 28 young-elderly patients treated with first line FIr-B/FOx: objective response rate (ORR) 79%, progression-free survival (PFS) 11 months, overall survival (OS) 21 months. Clinical outcome was not significantly different according to KRAS genotype. G3-4 toxicities were diarrhea 21%, mucositis 11%, neutropenia 11%. LTS were 46%, significantly more multiple than single site. At 8 months follow-up, in 37 unfit patients: ORR 37%, PFS 7 months, OS 13 months. PFS was significantly different in KRAS wild-type compared to mutant patients, while not OS. PFS and OS were significantly worse in KRAS c.35 G > A compared to wild-type and/or other mutant., Conclusions: Careful decision-making process including evaluation of patient's fitness, and individual safety should be included to select FIr-B/FOx intensive first line regimen in young-elderly MCRC patients. KRAS, and specifically c.35 G > A mutant genotype, may significantly affect clinical outcome in patients unfit for FIr-B/FOx.

Bevacizumab-containing chemotherapy differently predict increased efficacy in KRAS exon 2 mutant and wild-type metastatic colorectal cancer (MCRC) patients. Mutant compared to wild-type status did not significantly affect progression-free survival (PFS) and overall survival (OS) in patients fit for first line bevacizumab-containing FIr-B/FOx regimen, and after progression. In patients unfit for intensive regimens, mutant status significantly affected PFS, while not OS. Codon 12 KRAS mutations differentially affect GTPase function, and confer worse clinical behaviour. Prognostic relevance of the prevalent c.35 G>A KRAS mutation was retrospectively evaluated. Fit c.35 G>A mutant patients showed significantly worse OS compared to wild-type and to other mutant. After progression and in unfit patients, c.35 G>A mutation affected significantly worse PFS and OS. c.35 G>A mutant status does not significantly affect worse PFS in patients fit for first line FIr-B/FOx, and it may depend upon effectiveness of anti-VEGF-containing intensive regimen., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

First-line triplet chemotherapy plus bevacizumab (FIr-B/FOx) can improve efficacy of metastatic colorectal cancer (MCRC), KRAS wild-type and mutant. Prognostic relevance of KRAS genotype was evaluated in patients unfit for FIr-B/FOx, treated with conventional medical treatments. Consecutive MCRC patients not eligible for FIr-B/FOx regimen due to age (≥75 years) and/or comorbidities were treated with tailored conventional first-line treatments. KRAS codon 12/13 mutations were screened by direct sequencing. Activity and efficacy were evaluated and compared according to medical treatments, age (non-elderly and elderly≥65 years), comorbidity stage (Cumulative Illness Rating Scale), metastatic extension (liver-limited and other/multiple metastatic), and KRAS genotype, using log-rank. Selected first line treatments were medical in 37 patients (92.5%), and surgical in 3 patients (7.5%). Medical treatment regimens: triplet, 18 (45%); doublet, 15 (37.5%); mono-therapy, 4 (10%). At median follow-up of 8 months, objective response rate (ORR) was 37%, median progression-free survival (PFS) 7 months, liver metastasectomies 8% (liver-limited disease 37.5%), median overall survival (OS) 13 months. Triplet regimens failed to significantly affect clinical outcome, compared to doublet. According to KRAS genotype, ORR, PFS and OS were, respectively: wild-type 50%, 8 months, 13 months; mutant 25%, 6 months, 9 months. KRAS genotype wild-type compared to mutant significantly affected PFS, while not OS. KRAS c.35 G>A mutation (G12D) significantly affected worse PFS and OS compared to wild-type and/or other mutations. KRAS genotype, specifically the c.35 G>A KRAS mutation, may indicate poor prognosis in MCRC patients unfit for intensive medical treatments.

Clinical outcome post-progression to first-line triplet chemotherapy (CT) plus bevacizumab (FIr-B/FOx) was evaluated in metastatic colorectal cancer (MCRC) patients (pts). Second-line treatment was selected according to fitness, KRAS genotype, previous efficacy and safety. Efficacy was evaluated and compared according to treatment or KRAS genotype, using log-rank analysis. Among 54 pts, median overall survival (OS) post-progression was 12 months, significantly better in 40 (74.1%) treated compared to 14 (25.9%) who died without further treatment. Second-line surgical treatment, 4 pts (7.4%), medical treatment, 36 pts (66.7%): triplet CT plus targeted agent, 10 (18.5%); triplet regimens, 19 (35.2%); doublet/monotherapy, 7 (13%). At follow-up of 14 months, objective response rate (ORR) was 38%, metastasectomies 12.5%, progression-free survival (PFS) 10 months, OS 14 months. According to treatment, ORR, metastasectomies, PFS and OS were significantly favourable in triplet CT plus targeted agent compared to triplet, respectively: 80%, 40%, 13 months, not reached; 28%, 6%, 8 months, 11 months. PFS and OS were significantly worse in c.35 G>A mutant compared to wild-type and/or other mutant patients. Prognosis after progression to first‑line FIr-B/FOx may be significantly favourable in MCRC pts re-challenged with intensive regimens, and unfavourable in c.35 G>A KRAS mutant patients.

Background: Prognosis of KRAS wild-type and mutant metastatic colorectal cancer (MCRC) patients (pts) treated with bevacizumab (BEV)-containing chemotherapy is not significantly different. Since specific KRAS mutations confer different aggressive behaviors, the prognostic role of prevalent KRAS mutations was retrospectively evaluated in MCRC pts treated with first line FIr-B/FOx, associating BEV to triplet chemotherapy., Methods: Tumor samples were screened for KRAS codon 12, 13 and BRAF V600E mutations by SNaPshot and/or direct sequencing. MCRC pts <75-years-old were consecutively treated with FIr-B/FOx: weekly 12 hour-timed-flat-infusion/5-fluorouracil (900 mg/m(2) on days 1,2, 8, 9, 15, 16,22, 23), irinotecan plus BEV (160 mg/m(2) and 5 mg/kg, respectively, on days 1,15); and oxaliplatin (80 mg/m(2), on days 8,22). Pts were classified as liver-limited (L-L) and other/multiple metastatic (O/MM). Progression-free survival (PFS) and overall survival (OS) were compared using the log-rank test., Results: Fifty-nine pts were evaluated at a median follow-up of 21.5 months. KRAS mutant pts: c.35 G > A, 15 (25.4%); c.35 G > T, 7 (11.8%); c.38 G > A, 3 (5%); other, 3 (5%). KRAS wild-type, 31 pts (52.7%). The objective response rate (ORR), PFS and OS were, respectively: c.35 G > A mutant, 71%, 9 months, 14 months; other than c.35 G > A mutants, 61%, 12 months, 39 months. OS was significantly worse in c.35 G > A pts compared to KRAS wild-type (P = 0.002), KRAS/BRAF wild-type (P = 0.03), other MCRC patients (P = 0.002), other than c.35 G > A (P = 0.05), other codon 12 (P = 0.03) mutant pts. OS was not significantly different compared to c.35 G > T KRAS mutant (P = 0.142)., Conclusions: KRAS c.35 G > A mutant status may be significantly associated with a worse prognosis of MCRC pts treated with first line FIr-B/FOx intensive regimen compared to KRAS/BRAF wild type and other than c.35 G > A mutant pts.

Four-drug regimens, such as FIr-B/FOx schedule, can improve efficacy of first-line treatment of metastatic colorectal cancer (MCRC) patients. The present study specifically evaluates feasibility of FIr-B/FOx first-line intensive regimen in fit young-elderly MCRC patients, representing approximately 40% of overall MCRC patients. Activity, efficacy, and safety were equivalent to overall MCRC patients, not significantly different according to KRAS genotype. Clinical outcome was significantly prolonged in liver-limited compared to other/multiple metastatic disease. Safety evaluation of the individual young-elderly patient showed that limiting toxicity syndromes (LTS) in multiple sites were significantly increased, compared to LTS in single site, with respect to non-elderly patients.

A major problem concerning the addition of more drugs in a chemotherapy combination is designing a proper schedule assuring the balance between dose intensity of each drug, efficacy of the combination, and tolerability lessening the burden of drug toxicity. We evaluated triplet chemotherapy-based intensive regimens proposed as first-line treatment in patients with metastatic colorectal cancer. Using a FOLFOXIRI (5-fluorouracil [5-FU], irinotecan, and oxaliplatin) combination regimen, patients with metastatic colorectal cancer now have the possibility of longer survival, but disappointingly, with increased toxicities. Triplet chemotherapy regimen according to 5-fluorouracil, irinotecan /5-fluorouracil, oxaliplatin, characterized by timed flat-infusion 5-FU administration, without leucovorin, obtained efficacy equivalent to other reported similar combination regimens (5-FU, irinotecan, and oxaliplatin), with increased received 5-FU dose intensity and lower grade 3 to 4 neutropenia. To guarantee the proper balance between dose intensities, efficacy, and toxicity, triplet chemotherapy schedules could be further improved by abrogation of folinic acid and bolus 5-FU, a new and easy modality of 5-FU administration, such as timed flat-infusion 5-FU, associated with alternating irinotecan and oxaliplatin; this could favor diffusion of this intensive treatment in clinical practice., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Bevacizumab (BEV) plus triplet chemotherapy can increase efficacy of first-line treatment of metastatic colorectal cancer (MCRC), particularly integrated with secondary liver surgery in liver-limited (L-L) patients. The prognostic value of the KRAS genotype in L-L and other or multiple metastatic (O/MM) MCRC patients treated with the FIr-B/FOx regimen was retrospectively evaluated., Methods: Tumoral and metastatic samples were screened for KRAS codon 12 and 13 and BRAF mutations by SNaPshot and/or direct sequencing. Fit MCRC patients <75 years were consecutively treated with FIr-B/FOx regimen: weekly 12-h timed flat-infusion/5-fluorouracil (TFI 5-FU) 900 mg/m2, days 1, 2, 8, 9, 15, 16, 22 and 23; irinotecan (CPT-11) 160 mg/m2 plus BEV 5 mg/kg, days 1, 15; oxaliplatin (OXP) 80 mg/m2, days 8, 22; every 4 weeks. MCRC patients were classified as L-L and O/MM. Activity and efficacy were evaluated and compared using log-rank test., Results: In all, 59 patients 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 not significantly different. PFS and OS were significantly different in L-L compared to O/MM evaluable patients. In KRAS wild-type patients, clinical outcome of 12 L-L compared to 18 O/MM was significantly different: PFS 21 versus 12 months and OS 47 versus 28 months, respectively. In KRAS mutant patients, the clinical outcome of 13 L-L compared to 14 O/MM was not significantly different: PFS 11 months equivalently and OS 39 versus 19 months, respectively., Conclusions: The KRAS genotype wild-type and mutant does not significantly affect different clinical outcomes for MCRC patients treated with the first-line FIr-B/FOx intensive regimen. KRAS wild-type patients with L-L disease may achieve a significantly prolonged clinical outcome due to integration with secondary liver surgery, with respect to KRAS mutant patients.

This paper evaluates a recent study whereby a four-drug combination regimen adding bevacizumab to triplet fluorouracil, oxaliplatin and irinotecan chemotherapy is described for the first-line treatment of metastatic colorectal cancer. It extends the use of intensive medical treatments combining chemotherapy and the VEGF inhibitor bevacizumab, opening new perspectives for the design of four-drug intensive regimen-associating chemotherapy and targeted agents. In the future, these four-drug intensive regimens should be further improved for efficacy:toxicity ratio and verification in randomized trials.

Background: This phase II study investigated efficacy and safety of weekly alternating Bevacizumab (BEV)/Irinotecan (CPT-11) or Oxaliplatin (OHP) associated to weekly 5-Fluorouracil (5-FU) in first line treatment of metastatic colorectal carcinoma (MCRC)., Methods: Simon two-step design: delta 20% (p0 50%, p1 70%), power 80%, α 5%, β 20%. Projected objective responses (ORR): I step, 8/15 patients (pts); II step 26/43 pts. Schedule: weekly 12 h-timed-flat-infusion/5-FU 900 mg/m2, days 1-2, 8-9, 15-16, 22-23; CPT-11 160 mg/m2 plus BEV 5 mg/kg, days 1,15; OHP at three dose-levels, 60-70-80 mg/m2, days 8, 22; every 4 weeks., Results: Fifty consecutive, unselected pts < 75 years were enrolled: median age 63; young-elderly (yE) 24 (48%); liver metastases (LM) 33 pts, 66% Achieved OHP recommended dose, 80 mg/m2. ORR 82% intent-to-treat and 84% as-treated analysis. Median progression-free survival 12 months. Equivalent efficacy was obtained in yE pts. Liver metastasectomies were performed in 26% of all pts and in 39% of pts with LM. After a median follow-up of 21 months, median overall survival was 28 months. Cumulative G3-4 toxicities per patient: diarrhea 28%, mucositis 6%, neutropenia 10%, hypertension 2%. They were equivalent in yE pts. Limiting toxicity syndromes (LTS), consisting of the dose-limiting toxicity, associated or not to G2 or limiting toxicities: 44% overall, 46% in yE. Multiple versus single site LTS, respectively: overall, 24% versus 20%; yE pts, 37.5% versus 8%., Conclusion: Poker combination shows high activity and efficacy in first line treatment of MCRC. It increases liver metastasectomies rate and can be safely administered., Trial Registration: Osservatorio Nazionale sulla Sperimentazione Clinica dei Medicinali (OsSC) Agenzia Italiana del Farmaco (AIFA) Numero EudraCT 2007-004946-34.

A weekly administration of alternating irinotecan or oxaliplatin associated to 5-Fluorouracil in advanced colorectal cancer was planned in order to evaluate a new schedule maintaining dose intensities of each drug as in double combinations and tolerability of the triplet association. The following weekly schedule was administered: irinotecan, days 1 and 15; oxaliplatin, days 8 and 22; 5-fluorouracil (5-FU) over 12-h (from 10:00 p.m. to 10:00 a.m.) timed flat infusion, days 1-2, 8-9, 15-16 and 22-23, every 4 weeks. Dose- finding and phase II study were planned. Thirteen patients were enrolled in the dose-finding study and 23 in the phase II study. The recommended doses of our study are: irinotecan 160 mg/m(2); oxaliplatin 80 mg/m(2); 5-FU 900 mg/m(2). The dose-limiting toxicity was diarrhea (35% of patients) but no cases of febrile neutropenia were observed. In 30 patients assessable for response two complete (6.7%) and 18 partial (60%) responses were observed, for an overall response rate of 66.7% (alpha 0.05, CI+/-17). The triplet association using this weekly alternating schedule is an active and well-tolerated outpatient regimen. Surgical removal of residual disease was considered in 5 patients and a radical resection was performed in 5 patients (147 %).

Background: The aim of the study was to identify p53 gene mutations by FAMA (fluorescence-assisted mismatch analysis) in colorectal cancers., Patients and Methods: Analytical scanning of the p53 gene (exons 5-9) was performed in colon cancer samples from 44 consecutive patients by FAMA. FAMA is a semiautomatic scanning approach based on the chemical cleavage of the mismatch in fluorescently labeled heteroduplex DNA, obtained from the combination of a normal and a mutated allele. FAMA has already shown optimal levels of diagnostic accuracy and sensitivity in detecting gene mutations (nucleotide substitutions, insertions/deletions) both at the germline and somatic level. The peculiar feature of FAMA is its ability to detect and localize mutations, by a redundant pattern of signals due to fluorescent DNA fragments generated by chemical cleavage. Moreover, previous data have demonstrated that normal contaminating DNA from stromal cells in the sample does not affect the sensitivity of the procedure, leading to the identification of the mutation even when the ratio mutant/normal allele is 10%., Results: Eighteen mutations (12 missense, one nonsense, two deletions, three nucleotide substitutions at the level of the splice-junctions) and two polymorphisms were detected by FAMA in 17 patients (39%) and then confirmed by automated sequence analysis. Six of 18 mutations (33%) were not previously reported for colon cancer samples and two of 18 lesions (11%) were identified as novel p53 mutations., Conclusions: Analytical scanning of the p53 gene by FAMA in DNA from colon cancer samples provides a sensitive, accurate and specific diagnostic procedure for routine clinical application.

Background: Loss of TP53 function through gene mutation is a critical event in the development and progression of many tumour types including colorectal cancer (CRC). In vitro studies have found considerable heterogeneity amongst different TP53 mutants in terms of their transactivating abilities. The aim of this work was to evaluate whether TP53 mutations classified as functionally inactive (< or=20% of wildtype transactivation ability) had different prognostic and predictive values in CRC compared with mutations that retained significant activity., Materials and Methods: TP53 mutations within a large, international database of CRC (n = 3583) were classified according to functional status for transactivation., Results: Inactive TP53 mutations were found in 29% of all CRCs and were more frequent in rectal (32%) than proximal colon (22%) tumours (P < 0.001). Higher frequencies of inactive TP53 mutations were also seen in advanced stage tumours (P = 0.0003) and in tumours with the poor prognostic features of vascular (P = 0.006) and lymphatic invasion (P = 0.002). Inactive TP53 mutations were associated with significantly worse outcome only in patients with Dukes' stage D tumours (RR = 1.71, 95%CI 1.25-2.33, P < 0.001). Patients with Dukes' C stage tumours appeared to gain a survival benefit from 5-fluorouracil-based chemotherapy regardless of TP53 functional status for transactivation ability., Conclusions: Mutations that inactivate the transactivational ability of TP53 are more frequent in advanced CRC and are associated with worse prognosis in this stage of disease.

A dose-finding study was designed to determine the maximum tolerated dose (MTD) of a bimonthly 12-h (10:00 p.m to 10:00 a.m), timed flat infusion (TFI) of 5-fluorouracil (5-FU) plus irinotecan (CPT-11), without leucovorin (LV), for metastatic colorectal carcinoma (CRC). A total of 33 patients were treated. Seven dose levels included a fixed CPT-11 dose of 180 mg/m2 on days 1 and 15 (d(1,15)) and escalating doses of 5-FU 600-1200 mg/m2 on days 1-4 and 15-18 (d(1-4,15-18)). Dose-limiting toxicities (DLTs) were: grade 3-4 non-hematologic, grade 4 hematologic and any toxicity causing a more than a 2-week delay in treatment. The MTD was reached at the seventh dose level. DLTs were observed in 5/8 patients (63%): G3 diarrhea, 2 patients, associated with G3 mucositis in one instance; G4 neutropenia, 2 patients, associated with severe asthenia in 1 patient; G3 hand-foot syndrome, 1 patient. The recommended doses (RDs) were established at the sixth dose level: 5-FU, 1100 mg/m2/d(1-4,15-18); CPT-11 180 mg/m2/d(1,15) [5-FU and CPT-11 dose intensity (DI), 2200 and 90 mg/m2 per week (w), respectively]. At the recommended dose, the DLTs in 38 cycles were: mucositis, 2 cycles (5%); afebrile G4 neutropenia and hand-foot syndrome, 1 cycle (3%). In 24 assessable patients, the overall response rate was 37.5%. The present CPT-11/5-FU schedule is highly tolerable in an outpatient setting using the highest recommended 5-FU dose effective in advanced CRC.

Background: Oxaliplatin (L-OHP), active in a wide range of human and animal tumours, also CDDP-resistant, possesses unique molecular characteristics of action. However, the mechanisms by which the damage induced by L-OHP triggers a death signal are not yet fully defined., Materials and Methods: After L-OHP treatment of the HCT15 human colon cancer cell line, apoptosis was evaluated by DNA laddering detection and by flow cytometry; the effect on specific caspase-3, -8 and -9 inhibitors, mitochondrial membrane permeability transition, cytochrome C release and expression of CD95 and CD95L were also assessed., Results: HCT15 cells underwent apoptosis when treated with all used drug concentrations (7-25 microM). Treatment of cells with L-OHP resulted in the activation of caspase-8, -9 and -3, in a mitochondrial membrane depolarisation, and in an increase of CD95 receptor and CD95 ligand levels., Conclusion: The results correlated well with the ability of L-OHP to induce apoptosis and give further insights into the mechanisms underlying the L-OHP-induced apoptosis of tumor cells.

Ninety-six patients with colorectal cancer (stage B2-C) were randomized to the control arm or to receive adjuvant chemotherapy with folinic acid, FU and MMC. Ninety-three patients are evaluable. The median follow up is 12 months. The average time between surgery and the start of therapy is 28 days. Toxicity is evaluable in 36 of 41 treated patients. Four patients (10%) failed to complete the projected treatment due to toxicity. Toxicity observed in 208 courses of therapy was mostly gastrointestinal and hematological. No cases of treatment related death or cancer-associated hemolytic uremic syndrome (C-HUS) were reported. The average relative dose intensity (rDI) of the projected treatment was 82.6%. Our study is ongoing and further patients are required to achieve statistically significant results.