Plasma soluble VEGFR-1 is a potential dual biomarker of response and toxicity for bevacizumab with chemoradiation in locally advanced rectal cancer.

We explored plasma and urinary concentrations of two members of the vascular endothelial growth factor (VEGF) family and their receptors as potential response and toxicity biomarkers of bevacizumab with neoadjuvant chemoradiation in patients with localized rectal cancer. The concentrations of VEGF, placental growth factor (PlGF), soluble VEGF receptor 1 (sVEGFR-1), and sVEGFR-2 were measured in plasma and urine at baseline and during treatment. Pretreatment values and changes over time were analyzed as potential biomarkers of pathological response to treatment as well as for acute toxicity in patients with locally advanced rectal cancer treated prospectively in 2002-2008 with neoadjuvant bevacizumab, 5-fluorouracil, radiation therapy, and surgery in a phase I/II trial. Of all biomarkers, pretreatment plasma sVEGFR-1-an endogenous blocker of VEGF and PlGF, and a factor linked with "vascular normalization"-was associated with both primary tumor regression and the development of adverse events after neoadjuvant bevacizumab and chemoradiation. Based on the findings in this exploratory study, we propose that plasma sVEGFR-1 should be further studied as a potential biomarker to stratify patients in future studies of bevacizumab and/or cytotoxics in the neoadjuvant setting.

Total Neoadjuvant Therapy With FOLFIRINOX in Combination With Losartan Followed by Chemoradiotherapy for Locally Advanced Pancreatic Cancer: A Phase 2 Clinical Trial.

IMPORTANCE: Patients with locally advanced pancreatic cancer have historically poor outcomes. Evaluation of a total neoadjuvant approach is warranted. OBJECTIVE: To evaluate the margin-negative (R0) resection rate of neoadjuvant FOLFIRINOX (fluorouracil, leucovorin, oxaliplatin, and irinotecan) and losartan followed by chemoradiotherapy for locally advanced pancreatic cancer. DESIGN, SETTING, AND PARTICIPANTS: A single-arm phase 2 clinical trial was conducted at a large academic hospital from August 22, 2013, to May 22, 2018, among 49 patients with previously untreated locally advanced unresectable pancreatic cancer as determined by multidisciplinary review. Patients had Eastern Cooperative Oncology Group performance status 0 or 1 and adequate hematologic, renal, and hepatic function. Median follow-up for the analysis was 17.1 months (range, 5.0-53.7) among 27 patients still alive at study completion. INTERVENTIONS: Patients received FOLFIRINOX and losartan for 8 cycles. Patients with radiographically resectable tumor after chemotherapy received short-course chemoradiotherapy (5 GyE × 5 with protons) with capecitabine. Patients with persistent vascular involvement received long-course chemoradiotherapy (50.4 Gy with a vascular boost to 58.8 Gy) with fluorouracil or capecitabine. MAIN OUTCOMES AND MEASURES: R0 resection rate. RESULTS: Of the 49 patients (26 women and 23 men; median age 63 years [range, 42-78 years]), 39 completed 8 cycles of FOLFIRINOX and losartan; 10 patients had fewer than 8 cycles due to progression (5 patients), losartan intolerance (3 patients), and toxicity (2 patients). Seven patients (16%) had short-course chemoradiotherapy while 38 (84%) had long-course chemoradiotherapy. Forty-two (86%) patients underwent attempted surgery, with R0 resection achieved in 34 of 49 patients (69%; 95% CI, 55%-82%). Overall median progression-free survival was 17.5 months (95% CI: 13.9-22.7) and median overall survival was 31.4 months (95% CI, 18.1-38.5). Among patients who underwent resection, median progression-free survival was 21.3 months (95% CI, 16.6-28.2), and median overall survival was 33.0 months (95% CI, 31.4 to not reached). CONCLUSIONS AND RELEVANCE: Total neoadjuvant therapy with FOLFIRINOX, losartan, and chemoradiotherapy provides downstaging of locally advanced pancreatic ductal adenocarcinoma and is associated with an R0 resection rate of 61%. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01821729.

Investigation of the Lack of Angiogenesis in the Formation of Lymph Node Metastases.

BACKGROUND: To date, antiangiogenic therapy has failed to improve overall survival in cancer patients when used in the adjuvant setting (local-regional disease with no detectable systemic metastasis). The presence of lymph node metastases worsens prognosis, however their reliance on angiogenesis for growth has not been reported. METHODS: Here, we introduce a novel chronic lymph node window (CLNW) model to facilitate new discoveries in the growth and spread of lymph node metastases. We use the CLNW in multiple models of spontaneous lymphatic metastases in mice to study the vasculature of metastatic lymph nodes (n = 9-12). We further test our results in patient samples (n = 20 colon cancer patients; n = 20 head and neck cancer patients). Finally, we test the ability of antiangiogenic therapy to inhibit metastatic growth in the CLNW. All statistical tests were two-sided. RESULTS: Using the CLNW, we reveal the surprising lack of sprouting angiogenesis during metastatic growth, despite the presence of hypoxia in some lesions. Treatment with two different antiangiogenic therapies showed no effect on the growth or vascular density of lymph node metastases (day 10: untreated mean = 1.2%, 95% confidence interval [CI] = 0.7% to 1.7%; control mean = 0.7%, 95% CI = 0.1% to 1.3%; DC101 mean = 0.4%, 95% CI = 0.0% to 3.3%; sunitinib mean = 0.5%, 95% CI = 0.0% to 1.0%, analysis of variance P = .34). We confirmed these findings in clinical specimens, including the lack of reduction in blood vessel density in lymph node metastases in patients treated with bevacizumab (no bevacizumab group mean = 257 vessels/mm(2), 95% CI = 149 to 365 vessels/mm(2); bevacizumab group mean = 327 vessels/mm(2), 95% CI = 140 to 514 vessels/mm(2), P = .78). CONCLUSION: We provide preclinical and clinical evidence that sprouting angiogenesis does not occur during the growth of lymph node metastases, and thus reveals a new mechanism of treatment resistance to antiangiogenic therapy in adjuvant settings. The targets of clinically approved angiogenesis inhibitors are not active during early cancer progression in the lymph node, suggesting that inhibitors of sprouting angiogenesis as a class will not be effective in treating lymph node metastases.

HCC and angiogenesis: possible targets and future directions.

Hepatocellular carcinoma (HCC), the most common primary liver tumor, is notoriously resistant to systemic therapies, and often recurs even after aggressive local therapies. HCCs rely on the formation of new blood vessels for growth, and VEGF is critical in this process. A hallmark of new vessel formation in tumors is their structural and functional abnormality. This leads to an abnormal tumor microenvironment characterized by low oxygen tension. The liver is perfused by both arterial and venous blood and the resulting abnormal microenvironment selects for more-aggressive malignancies. Anti-VEGF therapy with sorafenib was the first systemic therapy to demonstrate improved survival in patients with advanced-stage HCC. This important development in the treatment of HCC raises hope as well as critical questions on the future development of targeted agents including other antiangiogenic agents, which hold promise to further increase survival in this aggressive disease.

Biomarkers of response and resistance to antiangiogenic therapy.

No validated biological markers (or biomarkers) currently exist for appropriately selecting patients with cancer for antiangiogenic therapy. Nor are there biomarkers identifying escape pathways that should be targeted after tumors develop resistance to a given antiangiogenic agent. A number of potential systemic, circulating, tissue and imaging biomarkers have emerged from recently completed phase I-III studies. Some of these are measured at baseline (for example VEGF polymorphisms), others are measured during treatment (such as hypertension, MRI-measured K(trans), circulating angiogenic molecules or collagen IV), and all are mechanistically based. Some of these biomarkers might be pharmacodynamic (for example, increase in circulating VEGF, placental growth factor) while others have potential for predicting clinical benefit or identifying the escape pathways (for example, stromal-cell-derived factor 1alpha, interleukin-6). Most biomarkers are disease and/or agent specific and all of them need to be validated prospectively. We discuss the current challenges in establishing biomarkers of antiangiogenic therapy, define systemic, circulating, tissue and imaging biomarkers and their advantages and disadvantages, and comment on the future opportunities for validating biomarkers of antiangiogenic therapy.