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1.
Br J Cancer ; 126(6): 874-880, 2022 04.
Article in English | MEDLINE | ID: mdl-34937947

ABSTRACT

BACKGROUND: Aflibercept is an antiangiogenic drug against metastatic colorectal cancer (mCRC) combined with 5-fluorouracil/leucovorin/irinotecan (FOLFIRI); however, no antiangiogenic biomarker has yet been validated. We assessed aflibercept plus FOLFIRI, investigating the biomarker role of baseline vascular endothelial growth factor A (VEGF-A) and angiotensin-converting enzyme (ACE). METHODS: Phase II trial in oxaliplatin-treated mCRC patients who received aflibercept plus FOLFIRI. The reported 135 ng/mL ACE cut-off was used and ROC analysis was performed to assess the optimal VEGF-A cut-off for progression-free survival (PFS). Overall survival (OS), time to progression (TTP), time to treatment failure (TTF), overall response rate (ORR) and disease control rate (DCR) were also assessed. RESULTS: In total, 101 patients were followed for a median of 12 (6-17) months. The 1941 pg/mL VEGF-A was an optimal cut-off, with a longer median PFS when VEGF-A was <1941 versus ≥1941 pg/mL (9 versus 4 months). Patients with VEGF-A < 1941 pg/mL showed longer median OS (19 versus 8 months), TTP (9 versus 4 months) and TTF (8 versus 4 months), along with higher ORR (26% versus 9%) and DCR (81% versus 55%). No differences were identified according to ACE levels. CONCLUSIONS: This study supports aflibercept plus FOLFIRI benefits, suggesting VEGF-A as a potential biomarker to predict better outcomes.


Subject(s)
Colorectal Neoplasms , Vascular Endothelial Growth Factor A , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers , Camptothecin/therapeutic use , Colorectal Neoplasms/pathology , Fluorouracil/therapeutic use , Humans , Irinotecan/therapeutic use , Leucovorin/therapeutic use , Receptors, Vascular Endothelial Growth Factor/therapeutic use , Recombinant Fusion Proteins/therapeutic use , Vascular Endothelial Growth Factor A/metabolism
2.
Drugs Aging ; 38(3): 219-231, 2021 03.
Article in English | MEDLINE | ID: mdl-33615402

ABSTRACT

BACKGROUND: Biologicals, in combination with chemotherapy, are recommended as first-line treatment of metastatic colorectal cancer (mCRC); however, evidence guiding the appropriate management of older patients with mCRC is limited. OBJECTIVE: This study was undertaken to compare the efficacy and safety outcomes in older versus younger patients with mCRC who received first-line biological therapy. METHODS: This retrospective analysis used pooled data from five trials undertaken by the Spanish Cooperative Group for the Treatment of Digestive Tumours. All were studies of adults with advanced CRC who received first-line treatment with chemotherapy plus bevacizumab, cetuximab or panitumumab, stratified by age (≥ 65 vs. < 65 years). Endpoints included progression-free survival (PFS), overall survival (OS), overall response rate (ORR) and safety. RESULTS: In total, 999 patients from five studies were included in the analysis: 480 (48%) were aged ≥ 65 years, and 519 (52%) were aged < 65 years. Median PFS did not differ significantly between patients aged ≥ 65 and < 65 years (9.9 vs. 9.4 months; hazard ratio [HR] 1.01; 95% confidence interval [CI] 0.88-1.17). Median OS was significantly shorter in older than in younger patients (21.3 vs. 25.0 months; HR 1.21; 95% CI 1.04-1.41). There was no significant difference between older and younger patients in ORR (59 vs. 62%). Patients aged ≥ 65 years experienced significantly more treatment-related grade 3 or higher adverse events (61.67%) than did patients aged < 65 years (45.86%). CONCLUSIONS: Biologicals plus chemotherapy is an effective first-line treatment option for selected patients aged ≥ 65 years with mCRC and has a manageable safety profile and efficacy comparable to that observed in younger patients.


Subject(s)
Biological Factors , Colorectal Neoplasms , Aged , Bevacizumab/adverse effects , Colorectal Neoplasms/drug therapy , Humans , Panitumumab , Retrospective Studies
3.
Clin Colorectal Cancer ; 19(3): e110-e116, 2020 09.
Article in English | MEDLINE | ID: mdl-32278676

ABSTRACT

BACKGROUND: Clinicopathologic characteristics and prognostic and predictive factors offer valuable guidance when selecting optimal first-line treatment in patients with metastatic colorectal cancer (CRC). The association between baseline circulating tumor cell (bCTC) count, molecular tumor profile, and clinicopathologic features was analyzed in a chemo-naïve metastatic CRC population. PATIENTS AND METHODS: A total of 1202 patients from the Spanish VISNÚ-1 (FOLFIRINOX/bevacizumab vs. FOLFOX/bevacizumab) and VISNÚ-2 (FOLFIRI/bevacizumab vs. FOLFIRI/cetuximab; RAS-wildtype) studies were analyzed for mutational status and bCTC count. The association between clinicopathologic characteristics and bCTC count, mutational status, and microsatellite instability (MSI) was analyzed in 589 eligible patients. RESULTS: Interestingly, 41% of the population studied presented ≥3 bCTC count. bCTC count ≥3 was associated with worse performance status (according Eastern Cooperative Oncology Group scale), stage IV at diagnosis, at least 3 metastatic sites, and elevated carcinoembryonic antigen (CEA) levels; but not with RAS or BRAF mutations or high MSI. BRAFmut (BRAF mutated) tumors were associated with right-sided primary tumors, peritoneum, distant lymph node metastasis, and less frequent liver involvement. RASmut (RAS mutated) was associated with worse performance status; stage IV at diagnosis; right-sided primary tumors; liver, lung, and bone metastases; at least 3 metastatic sites; and elevated CEA, whereas PIK3CAmut (PIK3CA mutated) tumors were associated with right-sided primary tumors, high CEA serum levels, and older age. High MSI was associated with right-sided primary tumors, distant lymph nodes metastasis, and lower CEA levels. CONCLUSIONS: In our study, elevated bCTCs and RASmut were associated with clinicopathologic features known to be associated with poor prognosis; whereas the poor prognosis of BRAFmut tumors in chemo-naïve metastatic CRC is not explained by associations with poor clinicopathologic prognostic factors, except right-sided primary tumors. TRIAL REGISTRATION NUMBER: VISNU 1 ClinicalTrials.gov ID: NCT01640405/ VISNU 2 ClinicalTrials.gov ID: NCT01640444.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Biomarkers, Tumor/genetics , Bone Neoplasms/drug therapy , Colorectal Neoplasms/drug therapy , Liver Neoplasms/drug therapy , Lung Neoplasms/drug therapy , Neoplastic Cells, Circulating , Adolescent , Adult , Aged , Bevacizumab/therapeutic use , Biomarkers, Tumor/blood , Bone Neoplasms/genetics , Bone Neoplasms/mortality , Bone Neoplasms/secondary , Camptothecin/analogs & derivatives , Camptothecin/therapeutic use , Cell Count , Colorectal Neoplasms/genetics , Colorectal Neoplasms/mortality , Colorectal Neoplasms/pathology , DNA Mutational Analysis , Female , Fluorouracil/therapeutic use , Humans , Irinotecan/therapeutic use , Leucovorin/therapeutic use , Liver Neoplasms/genetics , Liver Neoplasms/mortality , Liver Neoplasms/secondary , Lung Neoplasms/genetics , Lung Neoplasms/mortality , Lung Neoplasms/secondary , Male , Microsatellite Instability , Middle Aged , Mutation , Neoplasm Staging , Organoplatinum Compounds/therapeutic use , Oxaliplatin/therapeutic use , Prognosis , Progression-Free Survival , Prospective Studies , Proto-Oncogene Proteins B-raf/genetics , Risk Assessment/methods , Young Adult , ras Proteins/genetics
4.
Eur Urol Focus ; 3(4-5): 430-436, 2017 10.
Article in English | MEDLINE | ID: mdl-28753791

ABSTRACT

BACKGROUND: Markers able to predict the response to antiangiogenics in metastatic clear cell renal cell carcinoma (ccRCC) are not available. The development of new treatment options like immunotherapy are reaching the clinic; therefore, predictors of benefit from these different available treatments are increasingly needed. OBJECTIVE: In this study, we prospectively assessed the association of circulating endothelial cells (CECs) in peripheral blood with long-term benefit from first-line treatment in ccRCC. DESIGN, SETTING, AND PARTICIPANTS: A prospective observational study was designed involving 13 institutions of the Spanish Oncology Genitourinary Group. Adult patients diagnosed with advanced ccRCC who had achieved response or disease stabilization after 3 mo on first-line therapy were eligible. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: CECs were isolated from peripheral blood, captured with ferrofluids coated with monoclonal antibodies directed against the CD146 antigen, and assessed centrally with an automated standardized system. CECs were defined as 4',6-diamidino-2-phenylindole+, CD105+, and CD45-. Blood samples were systematically taken every 6 wk for 15 mo or until tumor progression, whichever occurred first. Clinical data were externally monitored at all centers. RESULTS AND LIMITATIONS: From August 9, 2011, to January 17, 2013, 75 patients were enrolled in the study. Patients with baseline CECs above the median showed a significantly longer progression-free survival than those with low CECs (22.2 mo vs 12.2 mo) with a hazard ratio of 2.5 (95% confidence interval: 1.2-5.3, p=0.016). There was no difference between CEC levels at baseline and at tumor progression (medians of 50 CECs/4ml and 52 CECs/4ml, respectively). CONCLUSIONS: Under antiangiogenic treatment, the detection of higher CEC levels is associated with clinical benefit in terms of progression-free survival in ccRCC. PATIENT SUMMARY: Antiangiogenics are the cornerstone of treatment in kidney cancer. Since they target endothelial rather than tumor cells, we studied the correlation between levels of circulating endothelial cells in peripheral blood and long-term benefit in patients on antiangiogenic therapy. Higher levels were associated with long-term benefit, suggesting that this determination could help to separate best responders from those who could require a more intensive approach.


Subject(s)
Biomarkers, Tumor/blood , Carcinoma, Renal Cell/drug therapy , Carcinoma, Renal Cell/pathology , Endothelial Cells/cytology , Endothelial Cells/drug effects , Adult , Aged , Aged, 80 and over , Angiogenesis Inhibitors/adverse effects , CD146 Antigen/metabolism , Cell Count/methods , Endoglin/metabolism , Female , Humans , Male , Middle Aged , Outcome Assessment, Health Care , Prospective Studies
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