A phase I dose-escalation study of oxaliplatin delivered via a laparoscopic approach using pressurised intraperitoneal aerosol chemotherapy for advanced peritoneal metastases of gastrointestinal tract cancers.

OBJECTIVE: The objectives were to define the maximum tolerated dose (MTD), safety profile and pharmacokinetics (PKs) of intraperitoneal oxaliplatin delivered by pressurised intraperitoneal aerosol chemotherapy (PIPAC) in patients with advanced peritoneal carcinomatosis from gastrointestinal tract cancers. METHODS: PIPAC was applied every 4-6 weeks, for 5 cycles, in a phase I dose-escalation study using a 3 + 3 design. The first dose level was 90 mg/m2 with planned increases of 50 mg/m2 per level. Platinum concentration was measured in plasma, tissues and intraperitoneal fluid samples. The trial was registered at ClinicalTrials.gov (NCT03294252). RESULTS: Ten patients with 33 PIPAC sessions were included. No dose limiting toxicity (DLT) occurred at 90 mg/m2 and two at 140 mg/m2. The MTD was therefore set at 90 mg/m2. Overall treatment included a median number of three PIPAC sessions (range: 1-5) and secondary complete cytoreductive surgery for two patients. Overall safety showed 67 grade I-II and 11 grade III-IV toxicities, usually haematologic, digestive (nausea/vomiting, abdominal pain), and fatigue. Oxaliplatin concentrations were three- to four-fold higher in tissue in contact with aerosol than in muscle without contact. At 140 mg/m2, the plasma oxaliplatin concentration was high with Cmax and area under the curve (AUC)0-48h of 1035 µg/l and 9028 µg h/L, respectively. CONCLUSIONS: The MTD of oxaliplatin during PIPAC is 90 mg/m2. PK data demonstrate a high tumour concentration and a significant systemic absorption.

Significant effect of VEGFA polymorphisms on the clinical outcome of metastatic colorectal cancer patients treated with FOLFIRI-cetuximab.

AIM: The efficacy of a cetuximab-based regimen used to treat metastatic colorectal cancer (mCRC) could be influenced by VEGFA polymorphisms. MATERIALS & METHODS: We studied the effects of five polymorphisms in the VEGFA gene (-2549D/I, -1154G/A, -460T/C, +405G/C and +936C/T) on the outcome of 98 mCRC patients treated with FOLFIRI plus cetuximab. RESULTS: Patients homozygous for the -2549D, -1154G and -460T alleles did exhibit higher response rates to treatment and longer progression-free survival compared with others. In addition, the DGTGC and IGCGC haplotypes were significantly associated with a lower risk of disease progression. CONCLUSION: These findings suggest that VEGFA genetic variations might influence response/resistance of FOLFIRI plus cetuximab treatment in mCRC patients.

A quantitative proteomic approach of the different stages of colorectal cancer establishes OLFM4 as a new nonmetastatic tumor marker.

Expression profiles represent new molecular tools that are useful to characterize the successive steps of tumor progression and the prediction of recurrence or chemotherapy response. In this study, we have used quantitative proteomic analysis to compare different stages of colorectal cancer. A combination of laser microdissection, OFFGEL separation, iTRAQ labeling, and MALDI-TOF/TOF MS was used to explore the proteome of 28 colorectal cancer tissues. Two software packages were used for identification and quantification of differentially expressed proteins: Protein Pilot and iQuantitator. Based on ∼1,190,702 MS/MS spectra, a total of 3138 proteins were identified, which represents the largest database of colorectal cancer realized to date and demonstrates the value of our quantitative proteomic approach. In this way, individual protein expression and variation have been identified for each patient and for each colorectal dysplasia and cancer stage (stages I-IV). A total of 555 proteins presenting a significant fold change were quantified in the different stages, and this differential expression correlated with immunohistochemistry results reported in the Human Protein Atlas database. To identify a candidate biomarker of the early stages of colorectal cancer, we focused our study on secreted proteins. In this way, we identified olfactomedin-4, which was overexpressed in adenomas and in early stages of colorectal tumors. This early stage overexpression was confirmed by immunohistochemistry in 126 paraffin-embedded tissues. Our results also indicate that OLFM4 is regulated by the Ras-NF-κB2 pathway, one of the main oncogenic pathways deregulated in colorectal tumors.

Cetuximab pharmacokinetics influences progression-free survival of metastatic colorectal cancer patients.

PURPOSE: An ancillary phase II study was conducted to study interindividual variability in cetuximab pharmacokinetics and its influence on progression-free survival (PFS) in metastatic colorectal cancer patients cotreated with irinotecan and 5-fluorouracil. EXPERIMENTAL DESIGN: Ninety-six patients received cetuximab as an infusion loading dose of 400 mg/m(2) followed by weekly infusions of 250 mg/m(2). Doses of irinotecan and 5-fluorouracil were adjusted individually. Cetuximab concentrations were measured by ELISA. Compartmental pharmacokinetic parameters were estimated by a population approach, and PFS was analyzed using a Cox model. RESULTS: Cetuximab pharmacokinetics was best described using a two-compartment model with both first-order and saturable (zero-order) elimination. Estimated pharmacokinetic parameters (% standard error) were as follows: central volume of distribution V(1) = 2.96 L (4%), peripheral volume of distribution V(2) = 4.65 L (6%), elimination clearance CL = 0.497 L/d (4%), distribution clearance Q = 0.836 L/d (8%), and zero-order elimination rate k(0) = 8.71 mg/d (10%). Body surface area influenced V(1), V(2), and k(0). Pretreatment serum albumin influenced CL. Risk of disease progression decreased with cetuximab global clearance (cumulative dose/cumulative area under the concentration versus time curve; P = 0.00016). Median PFS of patients with a cetuximab residual concentration on day 14 below median value was 3.3 months as compared with 7.8 months for the other patients (P = 0.004). CONCLUSIONS: Cetuximab pharmacokinetics in colorectal cancer patients can be described using a model combining linear and nonlinear elimination rates. PFS is influenced by global clearance of cetuximab, a parameter that can be estimated using cetuximab residual concentration on day 14.