Clinical significance of enterocyte-specific gene polymorphisms as candidate markers of oxaliplatin-based treatment for metastatic colorectal cancer.

Colorectal cancer (CRC) can be classified into subtypes based on gene expression signatures. Patients with stage III enterocyte subtype of the CRC Assigner classifier have been shown to benefit from oxaliplatin adjuvant therapy. Here, we investigated whether single nucleotide polymorphisms (SNPs) in two enterocyte subtype-related genes, MS4A12 and CDX2, could predict the efficacy of oxaliplatin in first-line treatment for patients with metastatic CRC (mCRC). Three cohorts of patients were included: a discovery cohort receiving FOLFOX ± bevacizumab (BEV) (n = 146), a validation cohort receiving FOLFOXIRI + BEV (n = 230), and a control cohort receiving FOLFIRI + BEV (n = 228). SNPs were analyzed by PCR-based direct sequencing. In the discovery cohort, MS4A12 rs4939378 and CDX2 rs3812863 were identified as potential markers of efficacy. In the validation cohort, any G allele of MS4A12 rs4939378 was associated with longer progression-free survival (PFS) than the A/A variant in both univariate analysis (12.4 vs. 10.9 months, hazard ratio [HR] 0.70, 95% confidence interval [CI] 0.49-0.99, P = 0.033) and multivariable analysis (HR 0.65, 95%CI 0.44-0.97, P = 0.035) in patients expressing wild-type KRAS, but not mutant KRAS. In contrast, longer PFS was observed for patients expressing the CDX2 rs3812863 G/G variant than any A allele in univariate analysis (32.3 vs. 10.3 months, HR 0.39, 95%CI 0.19-0.81, P = 0.004) only in patients expressing mutant KRAS. These findings were not observed in the control cohort. Thus, MS4A12 and CDX2 SNPs may have utility as predictive biomarkers of response to oxaliplatin-based treatment in mCRC patients.

PNN and KCNQ1OT1 Can Predict the Efficacy of Adjuvant Fluoropyrimidine-Based Chemotherapy in Colorectal Cancer Patients.

The benefit of adjuvant chemotherapy in the early stages of colorectal cancer (CRC) is still disappointing and the prediction of treatment outcome quite difficult. Recently, through a transcriptomic approach, we evidenced a role of PNN and KCNQ1OT1 gene expression in predicting response to fluoropyrimidine-based adjuvant chemotherapy in stage III CRC patients. Thus, the aim of this study was to validate in an independent cohort of stages IIIII CRC patients our previous findings. PNN and KCNQ1OT1 mRNA expression levels were evaluated in 74 formalin-fixed paraffin-embedded tumor and matched normal mucosa samples obtained by stages IIIII CRC patients treated with fluoropyrimidine-based adjuvant chemotherapy. PININ, the protein encoded by PNN, was immunohistochemically evaluated in 15 tumor and corresponding normal mucosa samples, selected on the basis of a low, medium, or high mRNA expression tumor/mucosa ratio. PNN and KCNQ1OT1 mRNA mean expression levels were significantly higher in tumor compared with normal tissues. Patients with high PNN or KCNQ1OT1 tumor mRNA levels according to ROC-based cutoffs showed a shorter disease-free survival (DFS) compared with patients with low tumor mRNA gene expression. Also, patients with tumor mRNA expression values of both genes below the identified cutoffs had a significantly longer DFS compared with patients with the expression of one or both genes above the cutoffs. In a representative large cohort of stages IIIII CRC untreated patients retrieved from GEO datasets, no difference in DFS was observed between patients with high and low PNN or KCNQ1OT1 gene expression levels. These data confirm our previous findings and underscore the relevance of PNN and KCNQ1OT1 expression in predicting DFS in early stages of CRC treated with fluoropyrimidine-based adjuvant chemotherapy. If further validated in a prospective case series, both biomarkers could be used to identify patients who benefit from this treatment and to offer alternative chemotherapy regimens to potential unresponsive patients. In relation to the suggested biological role of PNN and KCNQ1OT1 in CRC, they might also be exploited as potential therapeutic targets.

Management of Peritoneal Carcinomatosis With Cytoreductive Surgery Combined With Intraperitoneal Chemohyperthermia at a Novel Italian Center.

BACKGROUND: Peritoneal carcinomatosis (PC) is a common manifestation of many gastrointestinal (GI) malignancies and is an advanced stage that is often associated with disseminated disease. Considerable progress has been made to achieve safe elimination of macroscopic disease using cytoreductive surgery (CRS) and more recently in combination with hyperthermic intraperitoneal chemotherapy (HIPEC) for the treatment of microscopic disease or disease with minimal volume. The aim of this study was to assess the effects of such procedures on the quality of life (QoL), the long-term benefit and the functional status of the treated patients. PATIENTS AND METHODS: Data from patients who underwent CRS-HIPEC for peritoneal metastasis (PM) at our center from November 2016 to November 2018 were analyzed retrospectively. The drugs administered were mitomycin and cisplatin. Quality of life (QoL) was assessed using the Euroquol-5D-5L and National Comprehensive Cancer Network Functional Assessment of Cancer Therapy-Breast Cancer Symptom Index v2 questionnaires before CRS-HIPEC, and 1, 3 and 6 months after were administered. RESULTS: In our series, the survival efficacy of CRS plus HIPEC was confirmed in the treatment of primary and secondary peritoneal pathologies, particularly in ovarian cancer, although larger studies are needed to investigate its role in the pathology of gastric, colonic and rectal cancer. The QoL data were promising, with essentially stable values between the preoperative and the 1-month follow-up, but with incremental benefits from the second to the third month.

Prognostic impact of immune-microenvironment in colorectal liver metastases resected after triplets plus a biologic agent: A pooled analysis of five prospective trials.

BACKGROUND: Immune-contexture of tumour microenvironment (TME) influences prognosis of colorectal cancer (CRC) patients and can be altered by cytotoxic and targeted agents. Limited data are available regarding the immune-TME of CRC after treatment. METHODS: An extensive immunohistochemistry evaluation of immunological parameters on tumour cells and TME of colorectal liver metastases from 106 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (5-fluorouracil, oxaliplatin and irinotecan) or COI (capecitabine, oxaliplatin and irinotecan) plus bevacizumab (N = 59) or cetuximab (N = 47) in five first-line no-profit clinical trials was performed. RESULTS: No substantial differences were reported in immunological parameters according to administered targeted agent, RAS/BRAF mutational status and histopathological or Response Evaluation Criteria in Solid Tumours response. Stromal expression of Cyclooxygenase-2 (COX-2) (p = 0.002), Human leukocyte antigen (HLA) (p = 0.003) and Programmed cell death protein 1 (PD1) (p = 0.002) were independent prognostic factors for longer relapse-free survival (RFS) at multivariate analysis with a positive trend for post-resection overall survival (OS). Patients whose metastases expressed stromal COX-2, HLA and PD1 (inflamed-score positive) reported longer RFS (25.5 versus 9.8 months; p < 0.001) and post-resection OS (64.3 versus 37.7 months; p = 0.003) as compared with others. In addition, patients with higher expression of CD4 and CD8 T-cells in tumour core and invasive margin (CD4/CD8-score) showed a better post-resection OS (not-reached versus 41.6 months; p = 0.032). A combined score of inflamed-score and CD4/CD8-score (combo-score) showed a clear prognostic role. CONCLUSIONS: The present study emphasises the role of immune-TME as independent predictor of survival in patients resected after triplets plus biologic. Inflamed-, CD4/C8- and combo-scores should be confirmed as prognostic factors in further studies.

Upfront FOLFOXIRI plus bevacizumab and reintroduction after progression versus mFOLFOX6 plus bevacizumab followed by FOLFIRI plus bevacizumab in the treatment of patients with metastatic colorectal cancer (TRIBE2): a multicentre, open-label, phase 3, randomised, controlled trial.

BACKGROUND: The triplet FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab showed improved outcomes for patients with metastatic colorectal cancer, compared with FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus bevacizumab. However, the actual benefit of the upfront exposure to the three cytotoxic drugs compared with a preplanned sequential strategy of doublets was not clear, and neither was the feasibility or efficacy of therapies after disease progression. We aimed to compare a preplanned strategy of upfront FOLFOXIRI followed by the reintroduction of the same regimen after disease progression versus a sequence of mFOLFOX6 (fluorouracil, leucovorin, and oxaliplatin) and FOLFIRI doublets, in combination with bevacizumab. METHODS: TRIBE2 was an open-label, phase 3, randomised study of patients aged 18-75 years with an Eastern Cooperative Oncology Group (ECOG) performance status of 2, with unresectable, previously untreated metastatic colorectal cancer, recruited from 58 Italian oncology units. Patients were stratified according to centre, ECOG performance status, primary tumour location, and previous adjuvant chemotherapy. A randomisation system incorporating a minimisation algorithm was used to randomly assign patients (1:1) via a masked web-based allocation procedure to two different treatment strategies. In the control group, patients received first-line mFOLFOX6 (85 mg/m2 of intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab (5 mg/kg intravenously over 30 min) followed by FOLFIRI (180 mg/m2 of intravenous irinotecan over 120 min concurrently with 200 mg/m2 of leucovorin; 400 mg/m2 intravenous bolus of fluorouracil; 2400 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab after disease progression. In the experimental group, patients received FOLFOXIRI (165 mg/m2 of intravenous irinotecan over 60 min; 85 mg/m2 intravenous oxaliplatin concurrently with 200 mg/m2 of leucovorin over 120 min; 3200 mg/m2 continuous infusion of fluorouracil for 48 h) plus bevacizumab followed by the reintroduction of the same regimen after disease progression. Combination treatments were repeated every 14 days for up to eight cycles followed by fluorouracil and leucovorin (at the same dose administered at the last induction cycle) plus bevacizumab maintenance until disease progression, unacceptable adverse events, or consent withdrawal. Patients and investigators were not masked. The primary endpoint was progression-free survival 2, defined as the time from randomisation to disease progression on any treatment given after first disease progression, or death, analysed by intention to treat. Safety was assessed in patients who received at least one dose of their assigned treatment. Study recruitment is complete and follow-up is ongoing. This trial is registered with Clinicaltrials.gov, NCT02339116. FINDINGS: Between Feb 26, 2015, and May 15, 2017, 679 patients were randomly assigned and received treatment (340 in the control group and 339 in the experimental group). At data cut-off (July 30, 2019) median follow-up was 35·9 months (IQR 30·1-41·4). Median progression-free survival 2 was 19·2 months (95% CI 17·3-21·4) in the experimental group and 16·4 months (15·1-17·5) in the control group (hazard ratio [HR] 0·74, 95% CI 0·63-0·88; p=0·0005). During the first-line treatment, the most frequent of all-cause grade 3-4 events were diarrhoea (57 [17%] vs 18 [5%]), neutropenia (168 [50%] vs 71 [21%]), and arterial hypertension (25 [7%] vs 35 [10%]) in the experimental group compared with the control group. Serious adverse events occurred in 84 (25%) patients in the experimental group and in 56 (17%) patients in the control group. Eight treatment-related deaths were reported in the experimental group (two intestinal occlusions, two intestinal perforations, two sepsis, one myocardial infarction, and one bleeding) and four in the control group (two occlusions, one perforation, and one pulmonary embolism). After first disease progression, no substantial differences in the incidence of grade 3 or 4 adverse events were reported between the control and experimental groups, with the exception of neurotoxicity, which was only reported in the experimental group (six [5%] of 132 patients). Serious adverse events after disease progression occurred in 20 (15%) patients in the experimental group and 25 (12%) in the control group. Three treatment-related deaths after first disease progression were reported in the experimental group (two intestinal occlusions and one sepsis) and four in the control group (one intestinal occlusion, one intestinal perforation, one cerebrovascular event, and one sepsis). INTERPRETATION: Upfront FOLFOXIRI plus bevacizumab followed by the reintroduction of the same regimen after disease progression seems to be a preferable therapeutic strategy to sequential administration of chemotherapy doublets, in combination with bevacizumab, for patients with metastatic colorectal cancer selected according to the study criteria. FUNDING: The GONO Cooperative Group, the ARCO Foundation, and F Hoffmann-La Roche.

Angiogenesis Genotyping and Clinical Outcomes in Patients with Advanced Hepatocellular Carcinoma Receiving Sorafenib: The ALICE-2 Study.

BACKGROUND: Sorafenib represents one of the therapeutic strongholds for advanced hepatocellular carcinoma (HCC), but unfortunately, predictive factors are lacking. We previously reported that the VEGF single nucleotide polymorphisms (SNPs) rs2010963 and rs4604006 might correlate with clinical outcomes in sorafenib-treated HCC patients. OBJECTIVE: The objective of the ALICE-2 study is to define a prognostic angiogenesis profile to better identify HCC patients who are more likely to benefit from sorafenib treatment. PATIENTS AND METHODS: From 2008 to 2015, all consecutive HCC patients receiving sorafenib according to the Italian label were tested for specific HIF-1α, VEGF, and VEGFR SNPs. Results from angiogenesis genotyping were then correlated with clinical outcome parameters. RESULTS: Globally, a total of 210 patients were enrolled. At multivariate analysis rs12434438 of HIF1α, rs2010963 of VEGF-A, and rs4604006 of VEGF-C were confirmed as independent predictive factors. At the combined analysis of significant SNPs, the presence of two favourable alleles of rs2010963 and rs4604006 of VEGF compared to only one or to none favourable alleles, was able to identify three separate patients populations with different time-to-progression (TTP) (10.8 vs. 5.6 vs. 3.7 months, respectively; p < 0.0001) and overall survival (OS) (19.0 vs. 13.5 vs. 7.5 months, respectively; p < 0.0001). Furthermore, the presence of the GG genotype of rs12434438 (HIF-1α) seemed able to select a population with a particularly poor outcome, independently from the clinical effect of the two VEGF SNPs (TTP: 2.6 months, HR: 0.54, p = 0.0374; OS: 6.6 months, p = 0.0061, HR: 0.43). CONCLUSIONS: Our findings show that polymorphism analysis of HIF-1α, VEGF, and VEGFR genes may represent a prognostic panel to better identify HCC patients who are more likely to benefit from sorafenib treatment.

Pharmacological effects of the simultaneous and sequential combinations of trifluridine/tipiracil (TAS-102) and 5-fluorouracil in fluoropyrimidine-sensitive colon cancer cells.

The aim of this study was to investigate possible synergistic effects in vitro of trifluridine/tipiracil (TAS-102) and 5-fluoruracil (5-FU) on fluoropyrimidine-sensitive colon cancer cell lines of different mutational status in order to build a rational basis for the future use of this combination therapy in adjuvant settings or as a first-line treatment for metastatic disease. Proliferation assays were performed on HT-29 (B-raf mutated), SW-620 (ras mutated), and Caco-2 (wild type) colon cancer cell lines exposed to 120-h treatments of 5-FU, TAS-102 and their different combination schedules (simultaneous, sequential and reverse) at equimolar and non-equimolar ratios. The synergistic, additive and antagonistic effects of 5-FU and TAS-102 were determined by the combination index (CI) and dose reduction index (DRI). Our preclinical in vitro results may suggest an apparently counterintuitive but strongly synergistic combination of 5-FU and TAS-102 in fluoropyrimidine-sensitive colon cancer cells allowing a marked theoretical reduction in the administered doses of both drugs. In particular, this association seems to be highly effective in wild-type colon cancer cells, both in sequential and simultaneous schedules. Together, these data may build a rational basis for the future use of TAS-102 combined with 5-FU in adjuvant settings, or as a first-line treatment for metastatic disease.

Maintenance Therapy With Panitumumab Alone vs Panitumumab Plus Fluorouracil-Leucovorin in Patients With RAS Wild-Type Metastatic Colorectal Cancer: A Phase 2 Randomized Clinical Trial.

IMPORTANCE: Few studies are available on the role of maintenance strategies after induction treatment regimens based on anti-epidermal growth factor receptors, and the optimal regimen for an anti-epidermal growth factor receptors-based maintenance treatment in patients with RAS wild-type metastatic colorectal cancer is still to be defined. OBJECTIVE: To determine whether maintenance therapy with single-agent panitumumab was noninferior to panitumumab plus fluorouracil and leucovorin after a 4-month induction treatment regimen. DESIGN, SETTING, AND PARTICIPANTS: This open-label, randomized phase 2 noninferiority trial was conducted from July 7, 2015, through October 27, 2017, at multiple Italian centers. Patients with RAS wild-type, unresectable metastatic colorectal adenocarcinoma who had not received previous treatment for metastatic disease were eligible. Induction therapy consisted of panitumumab plus FOLFOX-4 (panitumumab, 6 mg/kg, oxaliplatin, 85 mg/m2 at day 1, leucovorin calcium, 200 mg/m2, and fluorouracil, 400-mg/m2 bolus, followed by 600-mg/m2 continuous 24-hour infusion at days 1 and 2, every 2 weeks). Cutoff date for analyses was July 30, 2018. INTERVENTIONS: Patients were randomized (1:1) to first-line panitumumab plus FOLFOX-4 for 8 cycles followed by maintenance therapy with panitumumab plus fluorouracil-leucovorin (arm A) or panitumumab (arm B) until progressive disease, unacceptable toxic effects, or consent withdrawal. The minimization method was used to stratify randomization by previous adjuvant treatment and number of metastatic sites. MAIN OUTCOMES AND MEASURES: The prespecified primary end point was 10-month progression-free survival (PFS) analyzed on an intention-to-treat basis with a noninferiority margin of 1.515 for the upper limit of the 1-sided 90% CI of the hazard ratio (HR) of arm B vs A. RESULTS: Overall, 229 patients (153 male [66.8%]; median age, 64 years [interquartile range (IQR), 56-70 years]) were randomly assigned to arm A (n = 117) or arm B (n = 112). At a median follow-up of 18.0 months (IQR, 13.1-23.3 months]), a total of 169 disease progression or death events occurred. Arm B was inferior (upper limit of 1-sided 90% CI of the HR, 1.857). Ten-month PFS was 59.9% (95% CI, 51.5%-69.8%) in arm A vs 49.0% (95% CI, 40.5%-59.4%) in arm B (HR, 1.51; 95% CI, 1.11-2.07; P = .01). During maintenance, arm A had a higher incidence of grade 3 or greater treatment-related adverse events (36 [42.4%] vs 16 [20.3%]) and panitumumab-related adverse events (27 [31.8%] vs 13 [16.4%]), compared with arm B. CONCLUSIONS AND RELEVANCE: In patients with RAS wild-type metastatic colorectal cancer, maintenance therapy with single-agent panitumumab was inferior in terms of PFS compared with panitumumab plus fluorouracil-leucovorin, which slightly increased the treatment toxic effects. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02476045.

Chemotherapeutic and antiangiogenic drugs beyond tumor progression in colon cancer: Evaluation of the effects of switched schedules and related pharmacodynamics.

The aim of the study was to evaluate the effects and the related pharmacological mechanisms of switched schedules of antiangiogenic and chemotherapeutic drugs beyond progression after a first-line treatment in a colorectal cancer preclinical model. In vivo studies were performed in nude mice subcutaneously transplanted with colon cancer cells. The treatments included drug combinations with a switch between chemotherapeutic (i.e., irinotecan and 5-fluorouracil) and/or antiangiogenic drugs (i.e., anti-VEGF antibodies and sunitinib) at the time of tumor progression. Proliferation assays were also achieved in vitro on different colon cancer cell lines exposed to SN-38 and sunitinib alone or in combination. ABCG2 gene expression was performed with real-time PCR and SN-38 intracellular concentrations were measured. The switch in the combined treatments, at the time of tumor progression, of the chemotherapeutic (from irinotecan to 5-fluoruracil), or the antiangiogenic drug (from anti-VEGF antibodies to sunitinib) or of both drugs induced a new response. Immunohistochemistry of stromal PDGF-C, PlGF, SD1-α, Tie-2, and VEGFR-2 showed statistical differences between tumors at the time of relapse and after the switched therapy. Moreover, the combination of SN-38 and sunitinib caused synergism on colon cancer cells, with significant inhibition of the ABCG2 gene expression and an increase of SN-38 intracellular concentrations. Our observations may be of clinical relevance, suggesting the switch of single chemotherapeutic or antiangiogenic drugs beyond progression of the disease to obtain a new tumor response due to a modulation of angiogenic factors and a direct effect on tumor cells with a possible variation of intracellular drug concentrations.

Atypical RAS Mutations in Metastatic Colorectal Cancer.

PURPOSE: To describe the clinical and molecular features of metastatic colorectal cancers (mCRCs) bearing uncommon atypical RAS (At-RAS) mutations at codons other than 12, 13, 59, 61, 117, and 146. MATERIALS AND METHODS: By exploiting five next-generation sequencing sources (Italian collaboration, Memorial Sloan Kettering Cancer Center, Samsung Medical Center, the Biomarker Research for Anti-EGFR Monoclonal Antibodies by Comprehensive Cancer Genomics (BREAC) study, and the Foundation Medicine database), we retrieved 175 At-RAS mutated cases. Molecular data were obtained from 163 samples from Memorial Sloan Kettering Cancer Center and the Foundation Medicine database. Clinical data were available for 27 At-RAS-positive and 467 negative cases from the Italian collaboration, Memorial Sloan Kettering Cancer Center, Samsung Medical Center, and the BREAC study. RESULTS: At-RAS mutations were identified in 163 (0.9%) of 18,270 mCRCs. Among 133 with evaluable microsatellite instability status, 11 (8%) were microsatellite instability high. POLE exonuclease domain mutations had higher frequency (7%) than expected and were found only in microsatellite-stable tumors with high tumor mutational burden (TMB). Overall, 17% (28 of 163) of At-RAS cases had TMB greater than 20 mutations/Mb. Co-occurring typical RAS/BRAF V600E mutations and NF1 mutations, presumed to cause RAS activation, were found in 30% and 12% of samples, respectively (up to 43% and 50%, respectively, in TMB-high samples). Patients with RAS/BRAF wild-type mCRC achieved a median overall survival (OS) of 42.1 months, whereas those harboring isolated At-RAS, typical RAS, or BRAF V600E mutations showed a median OS of 32.3, 30.0, and 17.9 months, respectively (P < .001). No significant OS difference (P = .240) was found between patients with At-RAS versus typical RAS-mutated mCRC. Only one of six patients evaluable for primary resistance to anti-epidermal growth factor receptors achieved tumor response. CONCLUSION: At-RAS mutations may be a marker for RAS pathway activation and can be associated with high co-occurrence of POLE exonuclease domain mutations.

Autophagy-related polymorphisms predict hypertension in patients with metastatic colorectal cancer treated with FOLFIRI and bevacizumab: Results from TRIBE and FIRE-3 trials.

PURPOSE: The most frequent bevacizumab-related side-effects are hypertension, proteinuria, bleeding and thromboembolism. To date, there is no biomarker that predicts anti-VEGF-associated toxicity. As autophagy inhibits angiogenesis, we hypothesised that single-nucleotide polymorphisms (SNPs) within autophagy-related genes may predict bevacizumab-mediated toxicity in patients with metastatic colorectal cancer (mCRC). PATIENTS AND METHODS: Patients with mCRC treated with first-line FOLFIRI and bevacizumab in two phase III randomised trials, namely the TRIBE trial (n = 219, discovery cohort) and the FIRE-3 trial (n = 234, validation cohort) were included in this study. Patients receiving treatment with FOLFIRI and cetuximab (FIRE-3, n = 204) served as a negative control. 12 SNPs in eight autophagy-related genes (ATG3/5/8/13, beclin 1, FIP200, unc-51-like kinase 1, UVRAG) were analysed by PCR-based direct sequencing. RESULTS: The FIP200 rs1129660 variant showed significant associations with hypertension in the TRIBE cohort. Patients harbouring any G allele of the FIP200 rs1129660 SNP showed a significantly lower rate of grade 2-3 hypertension compared with the A/A genotype (3% versus 15%, odds ratio [OR] 0.17; 95% confidence interval [CI], 0.02-0.73; P = 0.009). Similarly, G allele carriers of the FIP200 rs1129660 SNP were less likely to develop grade 2-3 hypertension than patients with an A/A genotype in the FIRE-3 validation cohort (9% versus 20%, OR 0.43; 95% CI, 0.14-1.11; P = 0.077), whereas this association could not be observed in the control cohort (12% versus 9%, OR 1.40; 95% CI, 0.45-4.04; P = 0.60). CONCLUSION: This is the first report demonstrating that polymorphisms in the autophagy-related FIP200 gene may predict hypertension in patients with mCRC treated with FOLFIRI and bevacizumab.

Sorafenib plus daily low-dose temozolomide for relapsed glioblastoma: a phase II study.

BACKGROUND: Bevacizumab has provided encouraging results in relapsed glioblastoma multiforme (GBM). Pre-clinical and clinical investigations also showed that continuous low-dose temozolomide has some antiangiogenic activity. Based on this evidence, a phase II trial was designed to investigate an oral regimen of sorafenib, an oral multikinase inhibitor, and metronomic temozolomide for relapsed GBM. PATIENTS AND METHODS: Forty-three patients (median age=60.0 years) naive for antiangiogenic agents received 400 mg sorafenib twice daily plus TMZ 40 mg/m(2)/day until disease progression. RESULTS: Toxicity, mostly grade 1-2, was manageable. Grade 3-4 toxicities were hand-foot syndrome (n=4), hypertension (n=2), and fatigue (n=3). Five patients (12%) achieved partial response, 18 (43%) stable disease, 20 (48%) showed progression. The median time-to-progression was 3.2 months, 6-month progression-free survival was 26%, and median overall survival was 7.4 months. CONCLUSION: This combination of sorafenib and temozolomide was feasible and safe, showing some activity in patients with relapsed GBM.

Adjuvant systemic chemotherapy after putative curative resection of colorectal liver and lung metastases.

OBJECTIVE: Marginal statistical evidence of efficacy of adjuvant and/or perioperative chemotherapy after resection of colorectal metastases exists, but formal recommendations are still lacking. The present study evaluated the adjuvant systemic chemotherapy after the first resection of liver and lung colorectal cancer metastases. PATIENTS AND METHODS: We retrospectively reviewed data of 181 consecutive unselected patients with R0 resection of colorectal metastases treated simultaneously at 2 institutions from 1997 to 2004. Patients > 75 years old, with an Eastern Cooperative Oncology Group Performance Status Score ≥ 2 or unfit for adjuvant chemotherapy were excluded from the analysis. The decision on chemotherapy after surgery was left to the patient in the absence of conclusive data on the efficacy of adjuvant chemotherapy in this setting. A total of 151 patients (131 with liver metastases, 20 with lung metastases), 78 of whom underwent adjuvant chemotherapy, were evaluable for disease-free survival (DFS) and overall survival. The main prognostic factors for DFS after resection of colorectal cancer metastases were investigated in univariate and multivariate analyses. RESULTS: At the univariate analysis, the number of resected lesions, lesion volume, disease-free interval and adjuvant systemic chemotherapy were the only significant prognostic factors. At multivariate analysis, only adjuvant chemotherapy and disease-free interval were independent prognostic factors (hazard ratios 1.66 and 1.62, respectively). The median DFS of patients who underwent systemic adjuvant chemotherapy was 16 months compared with 9.7 months for patients with observation alone (hazard ratio 1.56). Estimated 5-year DFS was 17.4% and 10.5% for treated and untreated patients, respectively. CONCLUSION: Adjuvant chemotherapy after metastasectomy in patients with colorectal cancer showed a significant benefit for DFS.

Chemotherapy: How useful is adjuvant irinotecan in stage IV CRC?

Patients who undergo hepatic surgery for initially resectable liver metastases from colorectal cancer have a 70% risk of relapse. a recent phase III randomized trial has failed to demonstrate an improvement in disease-free survival with the addition of irinotecan to 5-fluorouracil and folinic acid as adjuvant treatment for patients with radically resected colorectal cancer with liver metastases.

Use of pegfilgrastim support on day 9 to maintain relative dose intensity of chemotherapy in breast cancer patients receiving a day 1 and 8 CMF regimen.

AIM: In several commonly used regimens, chemotherapy doses are split across different days of the cycle. We aimed to determine the feasibility of growth factor support with once-per-cycle pegfilgrastim in this setting. METHODS: This phase II study in breast cancer patients assessed the utility of a single 6 mg subcutaneous dose of pegfilgrastim administered on day 9 of an intravenous (IV) "split" CMF (cyclophosphamide 600 mg/m(2), methotrexate 40 mg/m(2) and 5-fluorouracil 600 mg/m(2)) chemotherapy regimen administered on days 1 and 8 and repeated every 28 days for 6 cycles. RESULTS: Fifty-eight patients were enrolled, with 49 completing the study. For the primary endpoint, 48 patients (83%) received >or=85% of the relative dose intensity (RDI) of chemotherapy over all 6 cycles (95% confidence interval [CI], 71-91%). Across all chemotherapy cycles, 41 patients (71%) received all scheduled cycles on time and most patients (n=49, 84%) received >or=85% of the planned dose of all chemotherapy agents in all cycles. In total, 295/319 cycles (92%) were delivered on schedule and >or=85% of the planned dose of all chemotherapy agents were administered in 309/319 cycles (97%). Febrile neutropenia was reported in only 2 patients (3%). There were no grade 4 adverse events related to pegfilgrastim. DISCUSSION: Day 9 pegfilgrastim administration was well tolerated and provided effective protection against neutropenia in patients receiving IV CMF on days 1 and 8, allowing chemotherapy to be delivered on time and at the scheduled dose in most patients.

5-fluorouracil pharmacokinetics predicts disease-free survival in patients administered adjuvant chemotherapy for colorectal cancer.

PURPOSE: To evaluate 5-fluorouracil (5-FU) and 5-fluoro-5,6-dihydrouracil (5-FDHU) pharmacokinetics and disease-free survival (DFS) in colorectal cancer patients given 5-FU-based adjuvant chemotherapy within a nonrandomized, retrospective, pharmacokinetic study. EXPERIMENTAL DESIGN: One hundred fifteen patients including 72 men (median age, 63 years; range, 36-79 years) and 43 women (median age, 60 years; range, 36-73 years) received 6 cycles of l-leucovorin 100 mg/m(2)/day and 5-FU 370 mg/m(2)/day i.v. boluses (5 days every 4 weeks). Individual plasma concentrations of 5-FU and 5-FDHU were determined on day 1 of the first cycle with a validated high performance liquid chromatography method, and the main pharmacokinetic variables were determined. Follow-up of all patients was extended up to 5 years after the end of adjuvant chemotherapy, and DFS was recorded. Univariate and multivariate analyses were conducted to evaluate any correlation among 5-FU pharmacokinetics, clinical and pathologic variables, and DFS. RESULTS: The area under the time/concentration curve (AUC) of 5-FU was significantly lower in 58 subjects who recurred (7.5 +/- 2.9 h x mg/L) with respect to other patients (9.3 +/- 4.1 h x mg/L). Furthermore, AUC values lower than 8.4 h x mg/L together with lymph node involvement and the interruption of treatment or reduction of doses were identified as risk factors at univariate analysis. The completion of 6 cycles of adjuvant treatment without dosage modifications was the only independent risk factor at multivariate analysis, despite a trend toward significance for 5-FU AUC values (cutoff value, 8.4 hxmg/L) was observed (P = 0.06). CONCLUSIONS: Pharmacokinetics of 5-FU should be regarded as an important factor for predicting disease recurrence in colorectal cancers.

Limited sampling model for the analysis of 5-fluorouracil pharmacokinetics in adjuvant chemotherapy for colorectal cancer.

BACKGROUND: Administration of 5-fluorouracil may be associated with life-threatening toxicities, resulting from a reduced drug biotransformation to the inactive metabolite 5-fluoro-5,6-dihydrouracil. Patients with severe toxicities display significant alterations of 5-fluorouracil pharmacokinetics, the monitoring of which may be made easier by the availability of a limited sampling model (LSM). METHODS: LSMs for 5-fluorouracil and 5-fluoro-5,6-dihydrouracil therapeutic monitoring have been developed in 80 patients with colorectal cancer (training set) given 5-fluorouracil, 370 mg/m(2) per day as an intravenous bolus, plus leucovorin, 100 mg/m(2) per day, for 5 days every 4 weeks. Pharmacokinetic analysis was performed on plasma levels of 5-fluorouracil and 5-fluoro-5,6-dihydrouracil obtained on day 1 of the first cycle of chemotherapy, and backward stepwise regression analysis was used to determine the optimal LSM on the basis of bias (percentage mean prediction error [MPE]) and precision (percentage root mean square prediction error [RMSE]). RESULTS: An optimal model based on 2 time points was obtained (percentage MPE = 1.99% +/- 1.41%; percentage RMSE = 12.70% +/- 1.27%), and the predicted area under the time versus plasma concentration curve (AUC) was calculated as follows: predicted AUC (h x microg/mL) = 0.119 x C(5) + 1.436 x C(45) + 2.066, in which C(5) and C(45) are plasma concentrations of 5-fluorouracil at 5 and 45 minutes after drug administration, respectively. The application of this algorithm to pharmacokinetic analysis of plasma levels of 5-fluorouracil in 80 patients (test set) allowed a precise estimation of AUC (percentage MPE = -0.09% +/- 1.37%; percentage RMSE = 12.17% +/- 1.23%). The best LSM for 5-fluoro-5,6-dihydrouracil was characterized by a percentage MPE of -0.64% +/- 0.86% and a percentage RMSE of 7.64% +/- 0.81%, and the optimal sampling time points were 45 and 180 minutes. CONCLUSION: The current LSM allows a reliable assessment of drug exposure and improves the use of therapeutic drug monitoring for treatment optimization of 5-fluorouracil in patients with cancer.