Background: There are few background data on the impact of clinical factors on neurotoxicity and prognosis in patients treated with adjuvant capecitabine and oxaliplatin (CAPOX) chemotherapy. Methods: 102 stage II high-risk and stage III colorectal cancer patients were treated for 6 months with adjuvant CAPOX, then they were followed up. Associations between clinical variables, metabolic syndrome components, smoking and neurotoxicity were evaluated by the χ² test. The Kaplan-Meier product limit method was applied to graph disease-free survival (DFS). Univariate analysis was done with the log-rank test. Cox's proportional hazards regression was used to analyze the effect of several risk factors on DFS. Results: Significant associations were found between diabetes (p < 0.001), BMI (p = 0.01) and the occurrence of chronic neurotoxicity. After a median follow-up of 46 months, 14 patients (13.7%) had suffered recurrence. An analysis of the prognostic factors for DFS showed that prognosis is unfavorable for patients with high lymph-nodal involvement (HR: 5.23, p = 0.0007), diabetes (HR: 4.86; p = 0.03) and a BMI ≥25 (HR: 3.69, p = 0.002). Discussion: Common mediators in diabetes and obesity could be involved in peripheral neuropathy and in stimulating micro-metastases. Further studies are necessary to explain this interesting connection between diabetes, obesity and colon cancer.

Cetuximab is a monoclonal antibody to the EGFR that induces antibody-dependent cell cytotoxicity (ADCC) through Fcg receptors on immune cells. Although SNPs in genes encoding Fcg receptors are functionally relevant to cetuximab-mediated ADCC in colorectal cancer, a direct correlation between in vitro ADCC and clinical response to cetuximab is not defined. We therefore enrolled 96 consecutive metastatic colorectal cancer (mCRC) patients at diagnosis in a study that assessed FcgR status and cetuximab-mediated ADCC. Patients carrying the FcgRIIa H alleles 131H/H and 131H/R had significantly higher ADCC compared with patients with the 131R/R alleles (P ¼ 0.013). Patients carrying FcgRIIIa genotypes with the V alleles 158V/V and 158V/F displayed higher ADCC compared with patients carrying the 158F/F genotype (P ¼ 0.001). Progression-free survival of patients with an FcgRIIIa 158V allele was significantly longer compared with patients carrying 158F/F (P ¼ 0.05), whereas no significant difference was observed for overall survival. Twentyeight of 50 mCRC patients with wild-type KRAS received cetuximab. The average ADCC-mediated killing was 30% of assay targets for patients who experienced cetuximab complete or partial response, 21% in patients with stable disease and 9% in patients with progressive disease. To characterize basal natural killer (NK) activity, cytotoxicity was evaluated in 39 of 96 mCRC patients. Patients who responded to first-line treatment had higher NK-cell cytotoxicity. Thus, although limited to this cohort of patients, in vitro cetuximab-mediated ADCC correlated with FcgR polymorphisms and predicted cetuximab responsiveness.

Today, we are experiencing a real cultural revolution in the therapeutic approach to cancer of the colon - rectum, that by orphan disease, it is now becoming an important paradigm of scientific innovations and concepts. Survival of patients with metastatic colorectal cancer (m-CRC) has been significantly improved with the introduction of the monoclonal antibodies that have as target the vascular endothelial growth factor (VEGF) and the epidermal growth factor receptor (EGFR). The PD-1/PD-L1 pathway in cancer is implicated in tumors escaping immune destruction. This pathway is up -regulated in many tumours. Blockade of this pathway with anti-PD-1 and anti-PD-L1 agents has led to remarkable clinical responses in patients affected by many different types of cancer. The aim of this review is to evaluate the effects of addiction of biological agents to standard chemotherapy in the treatment of m-CRC. We can say that, among the various treatment options, the challenge of the future will be a better selection of the population, to ensure the best possible benefit from treatment with anti-VEGF drugs or anti-EGFR and a careful and customized planning of the therapeutic strategy for each patient.

Abstract:Oxaliplatin is a third-generation platinum compound that has shown a defi nite role in the management of colorectal cancer (CRC). Oxaliplatin in combination with fl uorouracil and leucovorin in the FOLFOX4 regimen represents a new standard of treatment in the adjuvant setting as well as for the metastatic disease. The combination of oxaliplatin with capecitabine in the XELOX regimen has been demonstrated to be not inferior to FOLFOX4 in metastatic patients, and it is under evaluation, with or without bevacizumab, in the post-surgical management of resected patients. FOLFOX4 and XELOX regimens represent a backbone on which to add new targeted drugs. Indeed, the combination of bevacizumab with either FOLFOX4 or XELOX signifi cantly prolonged the progression-free survival and overall survival in comparison with FOLFOX4 or XELOX combined with placebo in metastatic CRC patients, while FOLFOX4 plus cetuximab produced a signifi cantly greater activity than FOLFOX4 alone in metastatic CRC patients with K-RAS wild type.

This study is the first prospective long-term evaluation demonstrating that FDG PET is not only an early predictor of pathologic response but is also a valuable prognostic tool. Our results indicate the potential of FDG PET for optimizing multidisciplinary management of patients with LARC.

BACKGROUNDIn patients with metastatic colorectal carcinoma (MCC), capecitabine has demonstrated a superior response rate (RR), equivalent disease progression‐free (PFS) and overall survival (OS), and an improved overall tolerability profile compared with bolus 5‐fluorouracil/leucovorin (5‐FU/LV). The FOLFOX4 regimen, combining oxaliplatin with LV and bolus plus infusional 5‐FU (LV5FU2), has been shown to improve RR and PFS versus LV5FU2, and it was more effective and less toxic than irinotecan plus bolus 5‐FU/LV. Capecitabine (an oral fluoropyrimidine) may be an effective, well tolerated, and more convenient alternative to 5‐FU/LV in combination with oxaliplatin, especially in older patients.METHODSElderly (≥ 70 years) patients with MCC were treated with a 3‐weekly regimen of oxaliplatin at an initial dose of 85 mg/m2 intravenously on Day 1 plus capecitabine 1000 mg/m2 orally twice daily from Days 2 to 15 (XELOX regimen). In the absence of Grade ≥ 2 hematologic toxicity, oxaliplatin was increased to 100 mg/m2 in the second cycle, and in the absence of Grade ≥ 2 nonhematologic adverse events during Cycle 2, capecitabine was increased to 1250 mg/m2 twice daily in the third and subsequent cycles. After the first 35 patients (first series), the treatment protocol was amended so that only an oxaliplatin increase to 110 mg/m2 and 130 mg/m2 during Cycles 2 and 3, respectively, was planned in the remaining 41 patients (second series).RESULTSSeventy‐six patients with a median age of 75 years (range, 70–82 years) entered the current study. In the first series, the oxaliplatin dose was increased in 18 (51%) patients, and the capecitabine dose was increased in 4 (11%) patients. In the second series, the oxaliplatin dose was increased to 110 mg/m2 in 26 (63%) patients, and to 130 mg/m2 in 19 (46%) patients. In all, 2 complete and 29 partial responses were observed, for an overall RR of 41% (95% confidence interval [CI], 30–53%). The median PFS was 8.5 months (95% CI, 6.7–10.3 months), and the median OS was 14.4 months (95% CI, 11.9–16.9 months). In a multivariate analysis, the presence of disease symptoms affected both PFS and OS, whereas OS also was independently affected by male gender and disease spread. Age had no independent effect on PFS or OS. Five percent of patients developed Grade ≥ 3 hematologic toxicity during treatment, Grade 3 peripheral neuropathy occurred in 8% of patients, and severe hand‐foot syndrome in 13% of patients.CONCLUSIONSFit elderly patients with MCC showed a good RR to XELOX with only mild toxicity observed in most patients. XELOX, should, therefore be considered as an important therapeutic option for elderly patients with MCC. Cancer 2005. © 2005 American Cancer Society.

SummaryIn advanced gastric cancer, we investigated feasibility and activity of sequential chemotherapy with docetaxel after an intensive weekly regimen consisting of cisplatin, epidoxorubicin, fluorouracil, leucovorin (PELF) plus filgrastim. Chemotherapy-naive patients with relapsed or metastatic gastric cancer received 8 weekly administrations of chemotherapy with cisplatin 40 mg/m 2 , fluorouracil 500 mg/m 2 ,epidoxorubicin 35 mg/m 2 , 6S-steroisomer of leucovorin 250 mg/m 2 and glutathione 1.5 g/m 2 . On the other days filgrastim 5 µg kg -1 was administered by subcutanous injection. Subsequently, patients with partial response or stable disease received 3 cycles of docetaxel 100 mg/m 2 every 3 weeks. 40 patients have been enrolled and they are evaluable for response and toxicity. After the PELF regimen, 3 patients achieved complete response, 13 patients showed partial response, 21 patients had stable disease and 3 patients progressed (40% response rate; 95% CI 25% to 55%). After docetaxel, 9 out 34 patients improved the outcome (26.5%); 7 patients with stable disease achieved partial response and 2 patients with partial response achieved complete response. The overall response rate in the 40 patients was 57.5% (95% CI, 42.5% to 72.5%). The PELF regimen did not cause any grade IV toxicity, the most frequent grade III acute side-effects were thrombocytopenia and vomiting which occurred in the 10% of 320 PELF cycles. Docetaxel caused grade III-IV neutropenia and thrombocytopenia in the 10% and the 19% of cycles respectively. Fatigue was a frequent side-effect during both PELF and docetaxel chemotherapy. The sequential application of docetaxel after PELF chemotherapy gained major objective responses with manageable toxicity. This strategy is worth of further investigation in the setting of palliative or neoadjuvant chemotherapy.

The RDs for this biweekly regimen were: OXA 110 mg/m(2) plus IRI 175 mg/m(2) on day 1, and LFA 250 mg/m(2) plus 5-FU 800 mg/m(2) on day 2. This regimen appeared active in pretreated gastrointestinal malignancies, and it is worthy of being evaluated in advanced colorectal carcinoma after failure of 5-FU-based adjuvant or palliative treatment.