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Background: Emerging evidence supports tumor tissue-based comprehensive genomic profiling (CGP) in metastatic colorectal cancer (mCRC). Data on liquid biopsy-based circulating tumor DNA (ctDNA) CGP are scarce and mainly retrospective. Prospective comparison between the two tests is not currently available., Materials and Methods: The CAPRI 2-GOIM trial investigates efficacy and safety of ctDNA-driven, cetuximab-based sequence of three treatment lines in patients with RAS/BRAF V600E wild-type (WT) mCRC, as determined by the local laboratory. Before first-line therapy, CGP is carried out with FoundationOne (F1) CDx and F1 Liquid (F1L) CDx (324 genes) on tumor tissue DNA and plasma ctDNA, respectively., Results: For 2/207 (0.96%) patients, no ctDNA was detected by F1L CDx. No patient displayed tumor fraction (TF) below 1%, whereas elevated ctDNA (TF ≥ 10%) was detected among 140/205 (68.3%) patients. One thousand and thirteen genomic variants were identified. F1L CDx found KRAS, NRAS, or BRAF V600E alterations in 19 patients, whose tumors were classified as RAS/BRAF V600E WT by the local laboratory. Both F1 CDx and F1L CDx were available for 164/205 (80%) patients. A concordance of 61.4% between the two tests was observed. The concordance increased to 72.7% for F1L CDx with TF ≥ 10%. Concordance for genes potentially involved in anti-epidermal growth factor receptor resistance was found in 137/164 (83%) patients, increasing to 91.5% for F1L CDx with TF ≥ 10%. A higher number of genomic alterations was detected by F1L CDx compared with F1 CDx, including six cases with KRAS and NRAS alterations. Overall, 109/205 (53.2%) patients displayed at least one actionable genomic alteration (I to IIIB), according to the European Society for Medical Oncology Scale for Clinical Actionability of Molecular Targets (ESCAT)., Conclusion: Baseline liquid biopsy-based CGP is feasible, has high concordance with tumor tissue-based CGP, could better recapitulate tumor heterogeneity, and is clinically informative by identifying additional actionable genomic alterations in approximately half of RAS/BRAF V600E WT mCRC patients., (Copyright © 2024 European Society for Medical Oncology. Published by Elsevier Ltd. All rights reserved.)

Epidermal growth factor receptor (EGFR) inhibitors are valuable therapeutics in metastatic colorectal cancer (mCRC). Anti-EGFR monoclonal antibodies (MoAbs), such as cetuximab or panitumumab, in combination with chemotherapy are effective treatment options for patients with RAS and BRAF wild-type mCRC. Nevertheless, several issues are still open concerning the optimal use of anti-EGFR drugs in the continuum of care of mCRC. Novel approaches for increasing the efficacy of anti-EGFR therapies include better molecular selection of EGFR-dependent mCRC, intensification of chemotherapy, combination of anti-EGFR MoAbs and immune checkpoint inhibitors, and reintroduction of EGFR blockade or 'rechallenge' in selected patients who have previously responded to anti-EGFR MoAb therapy. An extensive translational research program was conducted in the Cetuximab After Progression in KRAS wIld-type colorectal cancer patients-Gruppo Oncologico dell' Italia Meridionale (CAPRI-GOIM) study with the aims of determining which subgroups of patients could benefit from the continuous inhibition of EGFR, from evaluating the role of liquid biopsy-based and its concordance with tissue-based molecular testing, and from investigating novel potential mechanisms of resistance to anti-EGFR therapies. In this review, we summarize the translational and clinical findings of the CAPRI-GOIM program in the context of the current knowledge of therapeutic strategies and of ongoing research on more appropriate uses of anti-EGFR therapies in RAS and BRAF wild-type mCRC patients., (Copyright © 2019 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: Cetuximab plus chemotherapy is a first-line treatment option in metastatic KRAS and NRAS wild-type colorectal cancer (CRC) patients. No data are currently available on continuing anti-epidermal growth factor receptor (EGFR) therapy beyond progression., Patients and Methods: We did this open-label, 1:1 randomized phase II trial at 25 hospitals in Italy to evaluate the efficacy of cetuximab plus 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) as second-line treatment of KRAS exon 2 wild-type metastatic CRC patients treated in first line with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) plus cetuximab. Patients received FOLFOX plus cetuximab (arm A) or FOLFOX (arm B). Primary end point was progression-free survival (PFS). Tumour tissues were assessed by next-generation sequencing (NGS). This report is the final analysis., Results: Between 1 February 2010 and 28 September 2014, 153 patients were randomized (74 in arm A and 79 in arm B). Median PFS was 6.4 [95% confidence interval (CI) 4.7-8.0] versus 4.5 months (95% CI 3.3-5.7); [hazard ratio (HR), 0.81; 95% CI 0.58-1.12; P = 0.19], respectively. NGS was performed in 117/153 (76.5%) cases; 66/117 patients (34 in arm A and 32 in arm B) had KRAS, NRAS, BRAF and PIK3CA wild-type tumours. For these patients, PFS was longer in the FOLFOX plus cetuximab arm [median 6.9 (95% CI 5.5-8.2) versus 5.3 months (95% CI 3.7-6.9); HR, 0.56 (95% CI 0.33-0.94); P = 0.025]. There was a trend in better overall survival: median 23.7 [(95% CI 19.4-28.0) versus 19.8 months (95% CI 14.9-24.7); HR, 0.57 (95% CI 0.32-1.02); P = 0.056]., Conclusions: Continuing cetuximab treatment in combination with chemotherapy is of potential therapeutic efficacy in molecularly selected patients and should be validated in randomized phase III trials., (© The Author 2016. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Treatment with antiepidermal growth factor receptor (anti-EGFR) monoclonal antibodies has been restricted to metastatic colorectal cancer (mCRC) patients with RAS wild-type tumors. Next-generation sequencing (NGS) allows the assessment in a single analysis of a large number of gene alterations and might provide important predictive and prognostic information., Patients and Methods: In the CAPRI-GOIM trial, 340 KRAS exon 2 wild-type mCRC patients received first-line FOLFIRI plus cetuximab. Tumor samples (182/340, 53.5%) were assessed by NGS to search for mutations in 22 genes involved in colon cancer., Results: Objective responses in the NGS cohort were observed in 104/182 patients [overall response rate (ORR) 57.1%; 95% confidence interval (95% CI) 52% to 66.4%] with a median progression-free survival (mPFS) of 9.8 (95% CI 8.7-11.5) months. NGS analysis was successfully completed in all 182 samples. One or more gene mutations (up to five) were detected in 124/182 (68.1%) tumors within 14/22 genes for a total of 206 mutations. KRAS exon 2 mutations were identified in 29/182 (15.9%) samples, defined as wild type by local laboratory assessment. Frequently mutated genes were: TP53 (39.6%), KRAS exons 3/4 (8.8%), NRAS exons 2/3 (7.1%), PIK3CA exons 9/20 (13.2%), BRAF (8.2%). FOLFIRI plus cetuximab treatment determined ORR of 62.0% (95% CI 55.5% to 74.6%) with mPFS of 11.1 (95% CI 9.2-12.8) months in patients with KRAS and NRAS wild-type tumors. Conversely, ORR was 46.6% (95% CI 39.9-57.5%) with mPFS of 8.9 (95% CI 7.4-9.6) months in patients with KRAS or NRAS mutations. Similarly, the subgroup of patients carrying KRAS, NRAS, BRAF, or PIK3CA mutations showed a worse outcome, although this might be due to a prognostic effect., Conclusions: This study demonstrates that NGS analysis in mCRC is feasible, reveals high level of intra and intertumor heterogeneity, and identifies patients that might benefit of FOLFIRI plus cetuximab treatment., (© The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Sorafenib is considered the standard systemic therapy for hepatocellular carcinoma (HCC), in patients with well-preserved liver function (Child-Pugh A class) and advanced-stage HCC (BCLC-C) or in patients with HCC progressing after locoregional therapies, with a high grade of recommendation. The approval of sorafenib for this indication was grounded on the efficacy and the safety results reported by two international randomized, controlled trials, the SHARP and the Asia-Pacific studies. In addition, the efficacy and the safety of sorafenib in clinical practice are addressed by several field-practice experiences, including the multinational GIDEON study and the SOFIA study. Finally, further research on sorafenib is ongoing to optimize the use of this molecule. This review aims to provide an overview of the most relevant clinical data on the efficacy and the safety of sorafenib in patients with HCC.

Background: This randomized, multicenter, phase III trial evaluated the efficacy and safety of the combination of epirubicin, leucovorin, 5-fluorouracil and etoposide (ELFE regimen) as adjuvant therapy for radically resected gastric cancer patients., Patients and Methods: From June 1996 to June 2001, 228 stage IB-IIIB gastric cancer patients were enrolled. All patients received a total or subtotal gastrectomy with at least a D1 lymphoadenectomy and were randomly assigned to receive surgery alone or surgery followed by chemotherapy., Results: A total number of 630 cycles was delivered with a median number of 5. With a median follow-up of 60 months, the 5-year overall survival (OS) was 48% in the treatment arm and 43.5% in the control arm [hazard ratio (HR) 0.91; 95% confidence interval (CI) 0.69-1.21; P = 0.610); the 5-year disease-free survival (DFS) was 44% in the treatment arm and 39% in the control arm (HR 0.88; 95% CI 0.78-0.91; P = 0.305). In node-positive patients, the 5-year OS was 41% in the treatment arm and 34% in the control arm (HR 0.84; 95% CI 0.69-1.01; P = 0.068), while the 5-year DFS was 39% in the treatment arm and 31% in the control arm (HR 0.88; 95% CI 0.78-0.91; P = 0.051). The most common grade 3-4 toxic effects according to World Health Organization criteria were hematological and gastrointestinal., Conclusions: In radically resected gastric cancer patients, adjuvant chemotherapy with ELFE regimen does not improve OS over surgery alone.

Historically, radiotherapy has been occasionally used in the treatment of gastric cancer. More recently, the results of INT-0116 trial have shown an improvement of disease-free and overall survival by chemoradiation with a significant impact on the management of this tumor. Based on these data, there has been an increasing interest in radiotherapy and its association with chemotherapy for patients with locoregional disease as a part of an adjuvant treatment after surgery in high-risk patients. However, many questions remain to evaluate; first of all the toxicity of this approach and its efficacy after adequate surgery.

Gastric cancer is still a major health problem and a leading cause of cancer mortality despite a worldwide decline in incidence. Surgery is the primary curative treatment of locoregional gastric cancer. In Western countries, however, at the time of resection, most patients are expected to have regional lymph node involvement with poor prognostic implications. To improve these results, different trials have been carried out in the adjuvant or neo-adjuvant setting. Many phase III trials of adjuvant therapy have been conducted; however, postoperative treatment modalities have not proven to be superior to postsurgical observation alone. Therefore, at present the routine use of adjuvant therapy should be regarded as an investigational approach. Improved clinical trial designs with standardized surgical techniques and the incorporation of newer active drugs are needed. On the contrary, neo-adjuvant chemotherapy has shown promising results as suggested by the final results of UK Medical Research Council Adjuvant Gastric Infusional Chemotherapy trial.

Background: Capecitabine and docetaxel have demonstrated preclinical antitumor synergy and activity in advanced gastric cancer. We assessed the clinical activity and the toxicity of weekly docetaxel in combination with capecitabine in untreated patients with advanced gastric cancer., Patients and Methods: A total of 38 patients were treated with docetaxel 36 mg/m2 on days 1, 8, and 15 i.v., plus capecitabine, 625 mg/m2 bid per os on days 5 to 18 repeated every 4 weeks., Results: All patients were assessable for response to treatment and for toxicity. Major responses were observed in eight patients (21%), with three patients achieving a CR (7.8%) and five showing a PR (13%). The median time to progression was 5.4 months and the overall survival was 7.7 months. The safety profile of this schedule was acceptable with a low rate of myelossuppression, diarrhoea and hand-foot syndrome., Conclusions: The combination of docetaxel and capecitabine at the doses and schedule investigated in this study is safe, but does not show significant activity in untreated patients with advanced gastric cancer.

Purpose: The primary end point of this phase III trial was to compare the response rate (RR) of oxaliplatin (OXA) plus levo-folinic acid (l-FA) and 5-fluorouracil (5-FU) bolus with that of irinotecan (IRI) plus l-FA and 5-FU bolus in advanced colorectal carcinoma., Patients and Methods: Patients with measurable metastatic colorectal carcinoma were randomly allocated to receive: IRI 200 mg/m(2) on day 1, l-FA 250 mg/m(2) intravenously plus 5-FU 850 mg/m(2) on day 2 (IRIFAFU); or OXA 100 mg/m(2) on day 1, l-FA 250 mg/m(2) plus 5-FU 1050 mg/m(2) on day 2 [OXAFAFU high dose (hd)]. Cycles were given every 2 weeks. After a planned interim analysis, OXA was reduced to 85 mg/m(2) and 5-FU to 850 mg/m(2) [OXAFAFU low dose (ld)]., Results: Two hundred and seventy-four patients (IRIFAFU, 135; OXAFAFUhd, 71; OXAFAFUld, 68) were treated. Forty-two confirmed responses were achieved with IRIFAFU, 29 with OXAFAFUhd and 32 with OXAFAFUld. The response rate with OXAFAFU [44%; 95% confidence interval (CI) 35% to 52%] was significantly higher (P=0.029) than that of IRIFAFU (31%; 95% CI 23% to 40%). Occurrence of grade > or =3 neutropenia with OXAFAFUld was similar to that for IRIFAFU (29% versus 31%), while severe diarrhoea was significantly lower (12% versus 24%). Median failure-free survival (7 versus 5.8 months; P=0.046) and overall survival of patients (18.9 versus 15.6 months; P=0.032) were significantly prolonged with OXAFAFU., Conclusions: OXAFAFU was more active and less toxic than IRIFAFU, and it should be preferred in the first-line treatment of advanced colorectal cancer patients.

Gastric cancer is still a major health problem and a leading cause of cancer mortality despite a worldwide decline in incidence. Surgical resection with curative potential is the only treatment modality of scientific proven effectiveness. Many phase III trials of adjuvant therapy have been conducted, however, postoperative treatment modalities have not proven to be superior to pos-surgical observation alone. Therefore, at present the routine use of adjuvant therapy should be regarded as an investigational approach. Improved clinical trial designs with standardized surgical techniques and the incorporation of newer active drugs are needed.

Background: Epidermal growth factor receptor (EGFR) inhibitors are in clinical development in cancer treatment. Preclinical studies have shown potential antitumor efficacy of these agents in combination with chemotherapy or with radiotherapy. However, controversial results have been obtained in different clinical trials., Materials and Methods: The effects on proliferation, cell cycle distribution and induction of apoptosis of three different anti-EGFR agents (gefitinib, ZD6474, cetuximab) were evaluated in different sequences of combination with either a platinum derivative (cisplatin, carboplatin, oxaliplatin) or a taxane (docetaxel, paclitaxel) in KYSE30 cells, a model of a human cancer cell line with a functional EGFR autocrine pathway., Results: The combination of a cytotoxic drug with an EGFR inhibitor caused different antiproliferative effects on KYSE30 cancer cells depending on the treatment schedule. An antagonistic effect was observed when treatment with each EGFR inhibitor was done before chemotherapy. In contrast, a synergistic antiproliferative activity was obtained when chemotherapy was followed by treatment with EGFR antagonists. This effect was accompanied by potentiation of apoptosis and arrest of the surviving cancer cells in the G(2)/M phases of the cell cycle., Conclusions: This study provides a rationale for the evaluation of a potentially synergistic sequence of cytotoxic drugs and EGFR inhibitors in a clinical setting.

Purpose: The purpose of this study was to compare the activity and toxicity of the combination of irinotecan (IRI) plus folinic acid (FA)-modulated 5-fluorouracil (5-FU) i.v. bolus with a regimen of double modulation of 5-FU with methotrexate (MTX) and FA in patients with advanced colorectal carcinoma., Patients and Methods: Two-hundred and thirty-four patients were enrolled: 118 patients received IRI 200 mg/m2 (90-min i.v. infusion) on day 1, followed by levo-FA 250 mg/m2 (2-h i.v. infusion) and 5-FU 850 mg/m2 (i.v. bolus) on day 2 (IRIFAFU), and 116 patients received MTX 750 mg/m2 (2-h i.v. infusion) on day 1, followed by levo-FA 250 mg/m2 (2-h i.v. infusion) and FU 800 mg/m2 (i.v. bolus) on day 2 (MTXFAFU). Both cycles were repeated every 2 weeks until progression or to a maximum of 16 cycles. Response rate (RR) was the main end point of the study; responses were assessed every four cycles and confirmed after 2 additional months of treatment., Results: RR was significantly greater with IRIFAFU (36%) than with MTXFAFU (20%) (P <0.001). Multivariate analysis showed that IRIFAFU was significantly associated with a greater activity (P = 0.028). Median progression-free survival was longer with IRIFAFU than with MTXFAFU (7.2 months compared with 4.8 months; P = 0.048). Median survival time (MST) did not differ between the two arms (14.7 months compared with 14.8 months, respectively). Patients not receiving second-line chemotherapy, however, lived longer when treated in the first-line with IRIFAFU (MST 11.9 months compared with 6.4 months; P = 0.038). IRIFAFU caused a significantly greater occurrence of grade 3 or 4 neutropenia (40% compared with 9%; P = 0.001) and diarrhoea (13% compared with 4%; P = 0.024), but a significantly lower incidence of stomatitis (3% compared with 12%; P = 0.007), than the comparative regimen., Conclusions: IRIFAFU appeared comparable in terms of activity and toxicity with other weekly or biweekly bolus or infusional combination regimens. IRIFAFU, however, seems easier to administer, because it does not require infusional catheter or pump devices, and it is less expensive. It may represent a new option for treating advanced colorectal carcinoma.

Purpose: The aim of this randomised trial was to evaluate the activity and toxicity of a biweekly regimen including 6S-leucovorin-modulated 5-fluorouracil (LFA-5-FU), combined with either irinotecan (CPT-11 + LFA 5-FU) or raltitrexed (Tomudex) (TOM + LFA-5-FU), in advanced colorectal cancer patients, and to make a preliminary comparison of both these experimental regimens with a biweekly administration of LFA-5-FU modulated by methotrexate (MTX + LFA-5-FU)., Patients and Methods: One hundred fifty-nine patients with advanced colorectal carcinoma previously untreated for the metastatic disease (34 of them previously exposed to adjuvant 5-FU) were randomly allocated to receive: CPT-11, 200 mg/m2 i.v. on day 1, followed on day 2 by LFA, 250 mg/m2 i.v. infusion and 5-FU, 850 mg/m2 s i.v. bolus (arm A); TOM, 3 mg/m2 i.v. on day 1, followed on day 2 by LFA, 250 mg/m2 i.v. infusion and 5-FU, 1050 mg/m2 i.v. bolus (arm B); or MTX, 750 mg/m2 i.v. on day 1, followed on day 2 by LFA, 250 mg/m2 i.v. infusion and 5-FU, 800 mg/m2 i.v. bolus (arm C). Courses were repeated every two weeks in all arms of the trial. Response rate (RR) was evaluated after every four courses. The sample size was defined to have an 80% power to detect a 35% RR for each experimental treatment, and to show a difference of at least 4% in RR with the standard treatment if the true difference is 15% or more., Results: The RRs were: 34% (95% confidence interval (95%, CI): 21%-48%) in arm A, including 3 complete responses (CRs) and 15 partial responses (PRs), 24% (95% CI: 14%-38%) in arm B, including 2 CRs and 11 PRs, and 24% (95% CI: 14%-38%), with 2 CRs and 11 PRs, in arm C. After a median follow-up time of 62 (range 18-108) weeks, the median time to progression was 38, 25, and 27 weeks for arm A, B, and C, respectively. With 94 patients still alive, the one-year probability of survival was 61%, 54%, and 59%, respectively. WHO grade 3 or 4 neutropenia and diarrhoea affected 46% and 16%, respectively, of patients treated with CPT-11 + LFA 5-FU. Median relative dose intensity over eight cycles (DI8) was 78% for CPT-11 and 82% for 5-FU. Severe toxicities of TOM + LFA-5-FU were neutropenia (16%) and diarrhoea (16%), but median relative DI8 was 93% for TOM, and 82% for 5-FU., Conclusions: CPT-11 + LFA-5-FU compares favorably in term of activity and toxicity with other combination regimens including CPT-11 and continuous infusional 5-FU. The hypothesis of a RR 15% higher than the MTX + LFA-5-FU treatment can not be ruled out after this interim analysis. The TOM + LFA 5-FU regimen showed a RR and a toxicity profile very close to the MTX + LFA 5-FU combination, and dose not deserve further evaluation in advanced colorectal cancer patients.

Purpose: To determine the maximum tolerated dose of oxaliplatin (L-OHP) given as a two-hour infusion followed by raltitrexed (Tomudex [TOM]) administered as a 15-min infusion on day 1, and bolus 5-fluorouracil (5-FU) modulated by a fixed dose of levo-folinic acid (LFA) 250 mg/m2 on day 2, recycling every two weeks, and to have preliminary evidence of activity of this combination in pretreated advanced colorectal cancer patients., Patients and Methods: Fifty-two patients with advanced colorectal carcinoma previously treated with one (25 cases) or two or more lines of chemotherapy, including irinotecan (26 cases), and/or modulated 5-FU (40 cases) entered this study. Starting doses of L-OHP, TOM, and 5-FU were 85, 2.5 and 750 mg/m2, respectively., Results: Seven dose levels were tested. Neutropenia was the main dose limiting toxicity of the dose escalation (8 of 13 cases). The recommended doses were 130 mg/m2 of L-OHP, and 3.0 mg/m2 of TOM on day 1, followed by 250 mg/m2 of LFA, and 1050 mg/m2 of 5-FU on day 2, every two weeks. Severe diarrhoea and stomatitis were rarely reported. Most patients complained of mild peripheral sensitive aeurotoxicity, which was related to the cumulative dose of L-OHP. Twelve patients were considered as having a major responses (one complete), and an additional eight patients showed a minor response; the median time to treatment failure was twenty-four weeks., Conclusions: With this regimen it is possible to give full doses of all three cytotoxic drugs every two weeks. Its activity and its manageable toxicity profile deserve further evaluation in pretreated advanced colorectal cancer patients.

Objectives: To determine the maximum tolerable doses (MTDs) of irinotecan (CPT-11) and 5-fluorouracil (5-FU) plus levofolinic acid (LFA) administered together every two weeks, to define the toxicity profile of this regimen, and to have a preliminary evidence of its activity in the first-line management of advanced colorectal cancer patients., Patients and Methods: Patients with histologically proven colorectal carcinoma, no prior chemotherapy for their advanced disease, and with at least one measurable or evaluable indicator lesion, were admitted to this study. The starting dose of CPT-11 was 150 mg/m2 given i.v. (90 min infusion) on day 1, followed on day 2 by a fixed dose of LFA (250 mg/m2) as a two-hour i.v. infusion plus a starting dose of 5-FU 600 mg/m2 as i.v. bolus. No intra-patient dose escalation was allowed. If no dose limiting toxicity (DLT) was observed among three patients of each cohort, CPT-11 and 5-FU were alternately escalated in the subsequent cohort. Otherwise, three more patients were enrolled at the same dose level. DLT was defined as: WHO grade 3 non-haematological toxicity (except for vomiting or alopecia), grade 3 febrile neutropenia, grade 4 neutro- or thombocytopenia, or a > 2-week delay in recycling. The MTDs were defined as the doses at which two of three, or four of six, patients showed the same DLT., Results: Thirty-one patients (five pretreated in adjuvant setting) were enrolled in this study, and a total number of 293 cycles (median 6/patient) were administered. Dose escalation safely proceeded to 210/950/250 mg/m2 of CPT-11/5-FU/LFA. These dosages were considered as MTDs, since four of six patients showed grade 4 neutropenia, in one case associated with grade 3 stomatitis. A mild decrease of both the CPT-11 and 5-FU doses to 200 and 850 mg/m2, respectively, caused different DLTs (neutropenia and diarrhoea) in two out of seven patients. At these dosages, transient grades 3 or 4 neutropenia affected two patients each during their treatment, while only one patient suffered from a severe delayed diarrhoea. Other non-haematological toxicities were mild and manageable. Therefore, we recommend this latter dose level for further study. Major responses (3 complete and 11 partial) were reported in 14 patients, for an overall response rate of 45% (95% CI: 27%-64%) according to an intent-to-treat analysis. Responses were observed from first dose level, and in four of five previously treated patients. Median failure-free and overall survivals, after a median follow-up of 39 weeks, were 42 and 55 weeks, respectively., Conclusions: The concurrent administration of CPT-11 and modulated 5-FU every two weeks is feasible at the recommended dosages. This regimen demonstrated interesting activity in the management of advanced colorectal cancer patients, and it probably better exploits the synergism between CPT-11 and 5-FU than recently tested alternating schedules. A phase II study is ongoing to more precisely define its activity and toxicity.