Bevacizumab improves survival in metastatic colorectal cancer patients with primary tumor resection: A meta-analysis

It is not well determined whether primary tumor resection is associated with better outcomes in metastatic colorectal cancer (mCRC) patients treated with bevacizumab. In this meta-analysis, we aimed to assess the prognostic role of primary tumor resection in mCRC treated with bevacizumab. Electronic databases including the Cochrane library, Embase, and Pubmed were searched until April 2018. Clinical studies assessing the influence of primary tumor resection on the efficacy of bevacizumab in patients with mCRC were identified. The primary endpoint was overall survival (OS), and the secondary endpoint was progression-free survival (PFS). Seven studies including 2760 mCRC patients were finally included. The results of the meta-analysis were in favor of bevacizumab to patients with resected primary tumor in terms of OS (HR = 0.50, 95%CI: 0.39–0.64; p < 0.01), and PFS (HR = 0.65, 95%CI: 0.51–0.81; p < 0.01). Administration of bevacizumab in mCRC patients with resected primary tumor had a better OS (HR = 0.65, 95%CI: 0.56–0.74; p < 0.01), when compared to chemotherapy(CT). Adding bevacizumab to mCRC patients without resection of primary tumor also had a better OS (HR = 0.78, 95%CI: 0.65–0.94; p < 0.01) and PFS (HR = 0.71, 95%CI: 0.57–0.88; p < 0.01) compared to chemotherapy alone. In conclusion, mCRC patients with resected primary tumor have better survival than those without surgery of primary tumor when treated with bevacizumab. Primary tumor resection status should be taken into consideration when using bevacizumab in mCRC.

PDTM-17. MiR-126, miR-369-5p AND miR-487b DRIVE PEDIATRIC GLIOBLASTOMA INVASION VIA KCNA1

Diffuse invasion is one of the key features that make GBM particularly difficult to treat. We hypothesize that direct comparison of matched invasive (GBMINV) and tumor core GBM cells (GBMTC) would facilitate the discovery of drivers of pediatric GBM (pGBM) invasion. However, GBMINV cells are extremely difficult to obtain from normal brain tissues because aggressive surgical resection of normal tissue carries the risk of serious neurological deficits. Most past and current studies on GBM invasion were and are forced to utilize the resected primary tumor masses. To overcome this barrier, we utilized a panel of 6 pediatric patient tumor-derived orthotopic xenograft (PDOX) mouse models to isolate matching pairs of GBMTC cells and GBMINV cells and confirmed a significantly elevated invasive capacity in GBMINV cells both in vitro and in vivo. Global profiling of 768 human microRNA using a real-time PCR-based Taqman system identified 23 microRNAs were upregulated in the GBMINV cells in at least 4 of the 6 pGBM models as compared with the matching GBMTC cells. We subsequently showed that silencing the top three miRNAINV, miR-126, miR-369-5p, and miR-487b, suppressed tumor cell migration in vitro (both as neurospheres and monolayer cultures) without affecting cell proliferation, and blocked pGBM invasion in mouse brains. Integrated analysis of the mRNA profiling of the same set of GBMTC and GBMINV cells revealed the affected signaling pathways and identified KCNA1 as the sole common computational target gene of the three miRNAINV. Treatment of three pairs of GBMTC and GBMINV cells with two KCNA1 inhibitors, ADWX1 and Agitoxin 2, caused significant suppression of pGBM cell migration in vitro. In conclusion, this study revealed an intrinsically elevated invasive phenotype in GBMINV cells, identified miR-126, -369-5p, and -487b as novel drivers of pGBM invasion, and characterized KCNA1 as a potential therapeutic target for arresting pGBM invasion.

Bevacizumab (BV) maintenance (M) after first-line chemotherapy (CT) plus BV for metastatic colorectal cancer (mCRC) patients (pts): A meta-analysis of individual pts data (IPD) from three phase III studies.

3550 Background: Although CAIRO3 and AIO KRK 0207 trials demonstrated the benefit of BV + fluoropyrimidine as a M regimen after induction CT + BV, the role of BV alone is not clear. Indeed, SAKK 41/06 and PRODIGE 9 trials failed to demonstrate the superiority of BV alone vs no M, while AIO KRK 0207 showed the non-inferiority of BV alone vs combo M. Thus, in order to evaluate the magnitude of the eventual benefit of M with BV alone vs no M, an IPD meta-analysis was performed. Methods: Trials whereas mCRC pts were prospectively randomized to receive BV M or not were considered eligible. Primary end-points were PFS and OS, both from the start of induction and M. Univariate and multivariate analyses for PFS and OS were performed, with the following variables: baseline ECOG PS; age ( > vs ≤ 65 years); RAS and BRAF status; LDH and CEA baseline level; RR (PR or CR vs SD) during induction; induction CT (oxa- vs iri-based); resected primary tumor; primary tumor side; synchronous vs metachronous; adjuvant treatment; number (N) of metastatic sites; liver-only disease. Results: IPD of 1,064 pts enrolled in the PRODIGE 9, AIO KRK 0207 and SAKK 41/06 trials were collected. Considering the different timing of randomization in PRODIGE 9 (at the start of induction) vs AIO KRK 0207 and SAKK 41/06 (at the start of M), IPD of pts not progressed during induction and starting M phase entered the analysis. 909 pts were included, 457 (50%) received BV M. Median PFS from induction start was 9.6 and 8.9 months in BV group vs no M group, respectively (HR 0.78; 95%CI: 0.68-0.89; p < 0.0001). At the multivariate PFS analysis, BV M, resected primary tumor, N of metastatic sites and liver-only disease were significant. No difference in terms of OS between the 2 groups was observed. Conclusions: This is the first IPD meta-analysis investigating the role of BV alone M vs no M after first-line induction CT+BV in mCRC pts. Despite the significant PFS improvement in favor of BV M, the absolute benefit appears limited, and without a clear clinical relevance. On these bases, a predictive nomogram to identify pts most likely to benefit from BV M is under evaluation and will be presented during the Congress.

Baseline predictors of survival in metastatic colorectal cancer.

e14105 Background: Patients with non-resectable metastatic colorectal cancer can survive several years with palliative chemotherapy and newer biological agents. However, survival varies greatly within this group. The aim of the present study was to identify baseline predictors of overall mortality in an unselected cohort of patients with metastatic colorectal cancer. Methods: Clinical information was collected from patient files in consecutive patients treated with palliative chemotherapy from August 2007 until June 2011. The primary outcome was overall survival. Cox regression analysis was used to examine the effect of predictive variables on time to outcome. The variables analysed were: Gender, age, performance status, primary tumor site (colon or rectum), status of primary tumor (resected or un-resected), metachronous metastases, more than two metastatic sites, liver-only metastases, and low albumin. Results: We included 314 patients (Median age 64.5 IQ (57-70) years, 194 (61.8%) male). Median follow-up for survival was 471 days IQ (257-708). One-year survival was 79%, CI (74-84%). Median overall survival was 676 days, CI (577-750). Following baseline variables were independent predictors of all-cause mortality: Primary tumor site colon HR: 1.49, CI (1.03-2.16), p=0.036, un-resected primary tumor HR 2.92, CI (1.85-4.62), p<0.001, metachronous metastases HR 1.72, CI (1.06-2.79), p=0.027 and more than two metastatic sites HR 3.46, CI (1.71-6.99), p=0.001. Both Performance status and low albumin were statistically significant in the univariate analysis, but not in the multivariate analysis. Conclusions: In daily clinical practice, baseline predictors of mortality in metastatic colorectal cancer were colon as the primary tumor site, un-resected primary tumor, metachronous metastases, and more than two metastatic sites.

Intensification of preoperative chemotherapy for osteogenic sarcoma: results of the Memorial Sloan-Kettering (T12) protocol.

PURPOSE It has been observed previously in osteosarcoma (OS) that the degree of necrosis of the resected primary tumor following a period of preoperative chemotherapy is predictive of subsequent event-free survival (EFS). The aim of this study was to determine if more intensive preoperative chemotherapy would increase the proportion of patients with a good histologic response and improve EFS. PATIENTS AND METHODS Seventy-three patients with OS were treated at Memorial-Sloan Kettering Cancer Center (MSKCC) on the T12 protocol between 1986 and 1993. Patients were randomized between therapy based on the T10 protocol and therapy with more intensive preoperative chemotherapy. The more intensive preoperative regimen consisted of two courses of cisplatin (CDDP) and doxorubicin (DOX) in addition to the usual preoperative regimen of high-dose methotrexate (HD MTX) and bleomycin, cyclophosphamide, and dactinomycin (BCD). RESULTS The regimen with more intensive preoperative chemotherapy achieved a modest increase in the proportion of patients with a good histologic response (44% with a grade III or IV histologic response v 37% in the control arm, 33% with grade IV histologic response v 13% in the control arm). EFS continued to correlate with histologic response. The actuarial 5-year EFS in patients with localized disease was 78% for the regimen with more intensive preoperative chemotherapy and 73% for the control arm. CONCLUSION Despite modest increases in the proportion of patients with good histologic response with intensified preoperative chemotherapy, no improvement in EFS was observed.