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Tumor kinase activity in locally advanced rectal cancer: angiogenic signaling and early systemic dissemination.

ABSTRACT: Tumor hypoxia is a common determinant of resistance to cytotoxic therapies and metastatic behavior. In rectal cancer patients receiving preoperative chemoradiotherapy, tyrosine kinase activities in tumors with poor and good treatment responses were found to differ. Given that tyrosine kinase signaling mediates hypoxic tissue adaptation, the present study examined whether tumor kinase activity might also correlate with systemic dissemination of rectal cancer. Immunomagnetic selection of disseminated tumor cells (DTC) from bone marrow aspirates was undertaken in 55 patients with locally advanced rectal cancer. Using peptide arrays with 144 tyrosine kinase substrates, phosphopeptide signatures were generated from patients' baseline tumor biopsies, to study association between DTC and tumor tyrosine kinase activity regulated ex vivo by sunitinib. Disseminated tumor cells were detected in 60% of cases, and these patients had significantly poorer metastasis-free survival than patients without DTC. Phosphorylation of 31 array tyrosine kinase substrates by tumor samples was significantly more strongly inhibited by sunitinib in the DTC-negative patients, with a number of phosphosubstrates representing angiogenic factors. In this cohort of rectal cancer patients, tumor phenotypes defined by a subset of tyrosine kinase activities correlating with weak ex vivo inhibition by sunitinib, was associated with early systemic dissemination.

SUBMITTER: Saelen MG

PROVIDER: S-EPMC3214264 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundPelvic radiation plus sensitizing chemotherapy with a fluoropyrimidine (chemoradiotherapy) before surgery is standard care for locally advanced rectal cancer in North America. Whether neoadjuvant chemotherapy with fluorouracil, leucovorin, and oxaliplatin (FOLFOX) can be used in lieu of chemoradiotherapy is uncertain.MethodsWe conducted a multicenter, unblinded, noninferiority, randomized trial of neoadjuvant FOLFOX (with chemoradiotherapy given only if the primary tumor decreased in size by <20% or if FOLFOX was discontinued because of side effects) as compared with chemoradiotherapy. Adults with rectal cancer that had been clinically staged as T2 node-positive, T3 node-negative, or T3 node-positive who were candidates for sphincter-sparing surgery were eligible to participate. The primary end point was disease-free survival. Noninferiority would be claimed if the upper limit of the two-sided 90.2% confidence interval of the hazard ratio for disease recurrence or death did not exceed 1.29. Secondary end points included overall survival, local recurrence (in a time-to-event analysis), complete pathological resection, complete response, and toxic effects.ResultsFrom June 2012 through December 2018, a total of 1194 patients underwent randomization and 1128 started treatment; among those who started treatment, 585 were in the FOLFOX group and 543 in the chemoradiotherapy group. At a median follow-up of 58 months, FOLFOX was noninferior to chemoradiotherapy for disease-free survival (hazard ratio for disease recurrence or death, 0.92; 90.2% confidence interval [CI], 0.74 to 1.14; P = 0.005 for noninferiority). Five-year disease-free survival was 80.8% (95% CI, 77.9 to 83.7) in the FOLFOX group and 78.6% (95% CI, 75.4 to 81.8) in the chemoradiotherapy group. The groups were similar with respect to overall survival (hazard ratio for death, 1.04; 95% CI, 0.74 to 1.44) and local recurrence (hazard ratio, 1.18; 95% CI, 0.44 to 3.16). In the FOLFOX group, 53 patients (9.1%) received preoperative chemoradiotherapy and 8 (1.4%) received postoperative chemoradiotherapy.ConclusionsIn patients with locally advanced rectal cancer who were eligible for sphincter-sparing surgery, preoperative FOLFOX was noninferior to preoperative chemoradiotherapy with respect to disease-free survival. (Funded by the National Cancer Institute; PROSPECT ClinicalTrials.gov number, NCT01515787.).

Project description:BackgroundA first pilot study showed that an image-guided navigation system could improve resection margin rates in locally advanced (LARC) and locally recurrent rectal cancer (LRRC) patients. Incremental surgical innovation is often implemented without reimbursement consequences, health economic aspects should however also be taken into account. This study evaluates the early cost-effectiveness of navigated surgery compared to standard surgery in LARC and LRRC.MethodsA Markov decision model was constructed to estimate the expected costs and outcomes for navigated and standard surgery. The input parameters were based on pilot data from a prospective (navigation cohort n = 33) and retrospective (control group n = 142) data. Utility values were measured in a comparable group (n = 63) through the EQ5D-5L. Additionally, sensitivity and value of information analyses were performed.ResultsBased on this early evaluation, navigated surgery showed incremental costs of €3141 and €2896 in LARC and LRRC. In LARC, navigated surgery resulted in 2.05 Quality-Adjusted Life Years (QALYs) vs 2.02 QALYs for standard surgery. For LRRC, we found 1.73 vs 1.67 QALYs respectively. This showed an Incremental Cost-Effectiveness Ratio (ICER) of €136.604 for LARC and €52.510 for LRRC per QALY gained. In scenario analyses, optimal utilization rates of the navigation technology lowered the ICER to €61.817 and €21.334 for LARC and LRRC. The ICERs of both indications were most sensitive to uncertainty surrounding the risk of progression in the first year after surgery, the risk of having a positive surgical margin, and the costs of the navigation system.ConclusionAdding navigation system use is expected to be cost-effective in LRRC and has the potential to become cost-effective in LARC. To increase the probability of being cost-effective, it is crucial to optimize efficient use of both the hybrid OR and the navigation system and identify subgroups where navigation is expected to show higher effectiveness.

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Tumor kinase activity in locally advanced rectal cancer: angiogenic signaling and early systemic dissemination.

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