Antiangiogenic Therapy In Patients Research Articles

Restriction spectrum imaging predicts response to bevacizumab in patients with high-grade glioma.

Diffusion-weighted imaging has shown initial promise for evaluating response to bevacizumab in patients with high-grade glioma (HGG). However, it is well recognized that the apparent diffusion coefficient (ADC) is influenced by bevacizumab-induced reductions in edema, which may limit its prognostic value. We demonstrate that an advanced diffusion-weighted imaging technique, restriction spectrum imaging (RSI), improves the evaluation of response to bevacizumab because unlike ADC, RSI is not affected by resolution of edema. RSI and ADC maps were analyzed for 40 patients with HGG prior to and following initiation of bevacizumab. Volumes of interest were drawn for regions of contrast enhancement (CE) and fluid attenuated inversion recovery (FLAIR) hyperintensity and histogram percentiles within volumes of interest were calculated for ADC 10th percentile (ADC-CE10%, ADC-FLAIR10%) and for RSI 90th percentile (RSI-CE90%, RSI-FLAIR90%). Cox proportional hazard models were used to evaluate the relationship between imaging parameters, progression-free survival (PFS), and overall survival (OS). An increase in RSI-FLAIR90% following bevacizumab was the strongest predictor of poor PFS (P= .016) and OS (P= .004), whereas decreases in ADC-FLAIR10% showed a weaker association with OS only (P= .041). Within the CE region, increases in RSI-CE90% alone were associated with poorer OS. Correlational analysis revealed that decreases in FLAIR volume were associated with decreases in ADC-FLAIR10%, but not with changes in RSI-FLAIR90%. RSI is less influenced by changes in edema, conferring an advantage of RSI over ADC for evaluating response to anti-angiogenic therapy in patients with HGG.

Early Assessment of Colorectal Cancer Patients with Liver Metastases Treated with Antiangiogenic Drugs: The Role of Intravoxel Incoherent Motion in Diffusion-Weighted Imaging.

PurposeTo assess the feasibility and effectiveness of quantitative intravoxel incoherent motion (IVIM) of Diffusion-weighted imaging (DWI) in the assessment of liver metastases treated with targeted chemotherapy agents.Methods12 patients with unresectable liver metastases from colorectal cancer were enrolled and received neoadjuvant FOLFIRI (5-fluorouracil, leucovorin, irinotecan) plus bevacizumab therapy. DWI was performed for 36 metastases at baseline and after 14 days from starting the treatment. In addition to the basic IVIM metrics, the product between pseudo-diffusivity and perfusion fraction was considered as a descriptor roughly analogous to the flow. Median diffusion parameters of Region of Interest (ROI) were used as representative values for each lesion. Normalized parameters in comparison with the median value of spleen were also collected. The percentual change of the diffusion parameters was calculated. The response to chemotherapy was evaluated according the Response Evaluation Criteria in Solid Tumors (RECIST) as calculated on whole-body CT scan obtained three months after treatment. Mann Whitney test and Receiver operating characteristic (ROC) analysis were performed.Results24 lesions were categorized as responding and 12 as not responding. There was no statistically significant difference among absolute and normalized diffusion parameters between the pretreatment and the post-treatment findings. Instead, the perfusion fraction (fp) values showed a statistical difference between responder and non-responder lesions: sensitivity and specificity of fp variation was 62% and 93%, respectively.ConclusionsIVIM parameters represent a valuable tool in the evaluation of the anti-angiogenic therapy in patients with liver metastases from colorectal cancer. A percentage change of fp represents the most effective DWI marker in the assessment of tumor response.

Upregulation of Nuclear Heat Shock Factor 1 Contributes to Tumor Angiogenesis and Poor Survival in Patients With Non–Small Cell Lung Cancer

The aim of this study was to detect the expression of heat shock factor 1 (HSF1) and microvessel density (MVD) in patients with non-small cell lung cancer (NSCLC) and to examine the relevance between HSF1 and angiogenesis, clinicopathologic factors, and prognosis. Immunohistochemical staining was used to examine the level of expression of HSF1 and CD34. MVD was used to detect the number of microvessels by counting CD34(+) endothelial cells. Their relationship with clinicopathologic factors and prognosis in patients with NSCLC was determined using IBM SPSS Statistics, version 19 (SPSS Inc, Chicago, IL). The level of expression of HSF1 was increased significantly in NSCLC. HSF1 overexpression was observed in 45 patients and was significantly associated with MVD (p= 0.005). The overexpression of HSF1 was not associated with patient sex, age, tumor size, histologic type, or differentiation, but it was significantly associated with node metastasis (p= 0.005) and clinical stage (p=0.006). HSF1 overexpression and high MVD were significantly associated with poor 5-year disease-free survival (p= 0.001 and p= 0.006, respectively). Patients with HSF1 overexpression and high MVD had a significantly poor overall survival (p= 0.006 and p= 0.019, respectively) and disease-specific survival (p= 0.005 and p= 0.016, respectively). Multivariate analysis showed that HSF1 overexpression was an independent prognosticator for poor overall, disease-specific, and disease-free survival (p= 0.040, p= 0.046, and p= 0.004, respectively). Overexpression of HSF1 is common and significantly correlated with tumor angiogenesis in NSCLC. Patients with high HSF1 expression had poorer overall, disease-free, and disease-specific survival. These current findings suggest that HSF1 may serve as a novel prognostic marker and potential therapeutic target molecule for antiangiogenic therapy in patients with NSCLC.

Increased expression of chitinase 3-like 1 is a prognosis marker for non-small cell lung cancer correlated with tumor angiogenesis.

Increasing evidence demonstrated that chitinase 3-like 1 (CHI3L1) was highly expressed and tightly associated with human tumor development and progression. However, its precise role in non-small cell lung cancer (NSCLC) remains to be delineated. The aim of this study was to examine CHI3L1 expression in patients with NSCLC and explore the relationship of CHI3L1 protein with clinicopathologic factors, tumor angiogenesis, and prognosis. CHI3L1 protein and intratumoral microvessels were examined by immunohistochemical staining in 95 NSCLC patients. Intratumoral microvessel density (MVD) was measured by counting CD34-positive immunostained endothelial cells. Quantitative real-time PCR (qRT-PCR) analyses were used to investigate the CHI3L1 expression status in tissues. Our result showed that CHI3L1 was significantly up-regulated in NSCLC tissues. In addition, univariate and multivariate analysis demonstrated that CHI3L1 protein overexpression and high MVD were significantly associated with tumor relapse. Although CHI3L1 overexpression and high MVD indicated poor overall survival (P < 0.05), multivariate analysis suggested that only CHI3L1 overexpression was an independent prognostic marker for unfavorable overall survival in patients with NSCLC (P < 0.05). The current results demonstrated that CHI3L1 may be a promising biomarker to identify individuals with poor prognostic potential and a possible target for anti-angiogenic therapy in patients with early stage NSCLC.

Antiangiogenic therapy for high-grade glioma.

The most common primary brain tumours in adults are gliomas. Gliomas span a spectrum from low to high-grade and are graded pathologically on a scale of one to four according to the World Health Organization (WHO) classification. High-grade glioma (HGG) carries a poor prognosis. Grade IV glioma is known as glioblastoma (GBM) and carries a median survival in treated patients of about 15 months. GBMs are rich in blood vessels (i.e. highly vascular) and in a protein known as vascular endothelial growth factor (VEGF), which promotes new blood vessel formation (the process of angiogenesis). Antiangiogenic agents inhibit the process of new blood vessel formation and promote regression of existing vessels. Several antiangiogenic agents have been investigated in clinical trials in newly diagnosed and recurrent HGG, showing promising preliminary results. This review was undertaken to report on the benefits and harms associated with the use of antiangiogenic agents in the treatment of HGGs. To evaluate the efficacy and toxicity of antiangiogenic therapy in patients with high-grade glioma. This intervention can be used in two broad groups of patients: those with first diagnosis as part of 'adjuvant' therapy, and those with recurrent or progressive disease. Comparisons will include the following.• Treatment with antiangiogenic therapy versus placebo.• Treatment (such as chemotherapy or chemoradiotherapy) with antiangiogenic therapy added versus the same treatment without the addition of antiangiogenic therapy. Searches were conducted to identify published and unpublished Randomised Controlled Trials (RCTs) starting in 2000; the following databases were searched: the Cochrane Central Register of Controlled Trials (CENTRAL), Issue 3, 2014; MEDLINE to April 2014 and EMBASE to April 2014. Proceedings of relevant oncology conferences since 2000 were handsearched. RCTs evaluating the use of antiangiogenic therapy versus control treatment without antiangiogenic therapy in the treatment of HGG. Review authors screened the search results and reviewed the abstracts of potentially relevant articles before retrieving the full text of eligible articles. After a comprehensive literature search, seven eligible RCTs were identified (total of 2987 participants). Significant design heterogeneity was noted in the included studies, especially in the response assessment criteria used. All eligible studies were restricted to GBMs, and no eligible studies evaluated other HGGs. Four studies were available only in abstract form. We have reserved an overall assessment of the quality of the evidence until the final study publications are received. The three studies that have been published in full were judged to have low risk of bias. The seven trials of 2987 participants included in this systematic review did not show improvement in OS with the addition of antiangiogenic therapy (pooled hazard ratio (HR) 0.94, 95% confidence interval (CI) 0.86 to 1.02; P value 0.16). However, pooled analysis of PFS from six studies (2847 participants) showed improvement in PFS with the addition of antiangiogenic therapy (HR 0.74, 95% CI 0.68 to 0.81; P value < 0.00001). Bevacizumab was the antiangiogenic therapy more likely to yield favourable results. Pooled HR for PFS for bevacizumab studies (three studies with 1712 participants) was significant at 0.66 (95% CI 0.59 to 0.74; P value < 0.00001), and this was reflected in the lower hazard ratio reported in the pooled analysis of bevacizumab studies compared with the overall analysis. Nevertheless, this finding was not significant for OS (HR 0.92, 95% CI 0.83 to 1.02; P value 0.12). Similar to trials of antiangiogenic therapies in other solid tumours, adverse events related to this class of therapy included hypertension and proteinuria, poor wound healing and the potential for thromboembolic events, although generally, the occurrence of grade 3 events of this kind was low (< 14.1%), consistent with reported findings of studies of bevacizumab in other tumours. In patients with newly diagnosed GBM, the use of antiangiogenic therapy does not improve survival, despite evidence of improved progression-free survival. Thus at this time, evidence is insufficient to support the use of antiangiogenic therapy in patients with newly diagnosed GBM on the basis of effects on survival.Bevacizumab may confer a progression-free survival benefit in GBM; however evidence in favour of using other antiangiogenic therapies in recurrent GBM is insufficient.Although bevacizumab appears to prolong progression-free survival in newly diagnosed and recurrent GBM, the impact of this on quality of life remains unclear.Adequately powered, randomised, placebo-controlled studies of bevacizumab in recurrent GBM (or HGG) are needed.Not addressed here is whether subsets of patients with newly diagnosed GBM may benefit from antiangiogenic therapies and whether these therapies are useful in other high-grade glioma histologies.

Molecular correlates of clinical benefit from antiangiogenic therapy for patients with lung adenocarcinoma: A hypothesis.

e22080 Background: Nintedanib, an oral triple-angiokinase inhibitor, in combination with docetaxel has demonstrated efficacy as a second-line treatment for NSCLC patients (pts) regardless of histol...

Radiation therapy and concurrent topotecan followed by maintenance triple anti-angiogenic therapy with thalidomide, etoposide, and celecoxib for pediatric diffuse intrinsic pontine glioma

Despite major treatment attempts, the prognosis for pediatric diffuse intrinsic pontine gliomas (DIPGs) remains dismal. Gliomas are highly vascularized tumors, suggesting that the prevention of vessel formation by anti-angiogenic treatment might be effective. Forty-one pediatric patients with DIPG were treated according to the Angiocomb protocol, starting with radiotherapy combined with topotecan and followed by anti-angiogenic triple medication consisting of thalidomide, etoposide, and celecoxib. Overall survival, radiological response, quality of life, requirement of corticosteroids, and adverse effects were monitored. Eight patients treated with only radiotherapy were used as controls. For study patients, the 12 and 24 months overall survival was 61% and 17%, respectively. The median overall survival was 12 months (range 4-60 months). Four radiological complete responses were seen, of which two were transient. Radiologically, 56% of the tumors reduced in size and 78% in signal intensity. Study patients were able to visit school or daycare and walk for a significantly longer time compared to controls (Log Rank 0.036 and 0.008, respectively). Adverse effects were generally minor. The Angiocomb protocol created a noticeable share of long-term survivors and was well tolerated, suggesting that anti-angiogenic therapy for patients with DIPG should be studied more in the future.

Pseudoprogression and Pseudoresponse in the Management of High-Grade Glioma : Optimal Decision Timing According to the Response Assessment of the Neuro-Oncology Working Group

ObjectiveWe evaluated pseudoprogression (PsPD) following radiation therapy combined with concurrent temozolomide (TMZ), and we assessed pseudoresponse following anti-angiogenic therapy for patients with recurrent disease using the Response Assessment of the Neuro-Oncology Working Group.MethodsPatients who were pathologically confirmed as having high-grade glioma received radiotherapy with concurrent TMZ followed by adjuvant TMZ. Bevacizumab (Avastin) with CPT-11 were used as a salvage option for cases of radiologic progression. Magnetic resonance imaging (MRI) was routinely performed 1 month after concurrent radiochemotherapy (CRT) and every 3 months thereafter. For cases treated with the bevacizumab-containing regimen for progressive disease, MRI was performed every 2 months.ResultsOf 55 patients, 21 (38%) showed radiologic progression within 4 weeks after CRT. Of these patients, 16 (29%) showed progression at second post-CRT MRI (etPD) and five (9%) showed improvement (PsPD). Seven of thirty-four initially non-progressed patients showed progression at the second post-CRT MRI (ltPD). No difference in survival was observed between the etPD and ltPD groups (p=0.595). Five (50%) of ten patients showed a radiological response after salvage bevacizumab therapy. Four of those patients exhibited rapid progression immediately after discontinuation of the drug (drug holiday).ConclusionTwelve weeks following treatment could be the optimal timing to determine PsPD or true progression. MRI with gadolinium enhancement alone is not sufficient to characterize tumor response or growth. Clinical correlation with adequate follow-up duration and histopathologic validation may be helpful in discriminating PsPD from true progression.

Combination of antiangiogenic therapy and cytotoxic chemotherapy for sarcomatoid renal cell carcinoma.

4512 Background: Numerous treatment options exist for metastatic renal cell carcinoma (mRCC), but optimal treatment for patients (pts) with sarcomatoid features remains undefined. Sarcomatoid differentiation is a particularly unfavorable prognostic feature in mRCC. Cytotoxic chemotherapy has modest activity, with a response rate of 16% for doxorubicin plus gemcitabine (Gem). Retrospective data has suggested a response rate of 10% for antiangiogenic therapy. We prospectively studied the combination of antiangiogenic therapy, sunitinib (Su), with Gem chemotherapy in this mRCC subpopulation. Methods: Pts with mRCC and sarcomatoid differentiation were enrolled in a phase 2 clinical trial at 3 institutions. Treatment consisted of 21-day cycles of Su, 37.5 mg on a 2 weeks on/1 week off schedule, along with Gem 1000 mg/m2 on days 1 and 8. The primary endpoint was radiographic response rate (RR) by RECIST. Secondary endpoints included time to disease progression (TTP), safety, and overall survival (OS). Results: Among 35 pts treated in total, 7 were classified as MSKCC good risk, 26 as intermediate risk, and 2 as poor risk. There were 10 partial responses and 1 complete response, for a confirmed RR of 30%. An additional 10 pts exhibited stable disease (clinical benefit rate 60%). Among the 10 pts who had progressive disease as their best response, the majority had underlying non-clear cell histology. Median TTP was 3.5 months (range 0.5-12). Eight pts discontinued due to adverse events (AEs). The most common treatment-emergent grade 3 or higher AEs were neutropenia (8 pts), fatigue (5), anemia (2), and hypertension (2). No treatment-related deaths occurred. Median OS was 11 months (range 1-38+). Conclusions: To our knowledge, this is the largest prospective trial combining cytotoxic chemotherapy and antiangiogenic therapy in patients with RCC and sarcomatoid features. Our results suggest that combination therapy may be more efficacious than either treatment alone in this subtype of mRCC and supports an ongoing intergroup trial (NCT01164228). Further research is necessary to define prognostic factors, including histologic and molecular biomarkers, for distinct subpopulations within this heterogeneous disease. Clinical trial information: NCT00556049.

Phase II study of low-dose peginterferon alfa-2b antiangiogenic therapy in patients with metastatic melanoma overexpressing basic fibroblast growth factor: An Eastern Cooperative Oncology Group study (E2602).

9038 Background: FGF-2 plays an important role in the pathogenesis and progression of melanoma. In particular, FGF-2 and its receptor are expressed in melanoma cells. We investigated the use of graded dosages Peg-IFN in patients with stage IV melanoma overexpressing FGF-2. Primary objective: suppression of plasma FGF-2 to normal levels (&lt; 7.5 pg/mL). Secondary objectives: clinical efficacy of Peg-IFN and its association with angiogenic factor levels (FGF-2 and vascular endothelial growth factor /VEGF). Methods: Patients were eligible if they had stage IV melanoma from any primary site. Prior systemic therapies (&lt; 4) were allowed including IFN. Plasma FGF-2 was measured at baseline (Step 1) and patients with levels &gt; 15 pg/mL allowed to receive study treatment (Step 2). Peg-IFN was given weekly at starting dose of 0.5 mcg/kg/wk with increments every 3 weeks (maximum dose: 5 mcg/kg/wk) based on serial FGF-2 levels. Results: 207 patients entered into Step 1 and 45 (22%) overexpressed FGF-2 with a median level of 22 pg/dL (range, 15-216). 29 eligible patients enrolled into Step 2 and received treatment. The median age was 64 years and most had &gt; 2 prior therapies. FGF-2 decreased in 28 (97%) patients with suppression to normal level in 10 (35%). The median time to FGF-2 suppression was 30 days (range, 14-116). The best clinical responses were PR (7%) and stable disease (17%). The median PFS and OS were 2.0 and 9.7 months, respectively. Patients who achieved FGF-2 suppression were more likely to have a response or stable disease compared to those who did not (50% vs 11%; P=.03). Landmark analysis at 63 days showed similar OS between those who achieved FGF-2 suppression and those who did not (7.8 vs 7.7 months; P=.31). VEGF decreased in 27 patients (93%) during treatment and the levels paralleled those of FGF-2 over time. We did not find a compensatory rise in VEGF level among those with FGF-2 suppression. Conclusions: Graded dose Peg-IFN suppresses FGF-2 and has activity against metastatic refractory melanoma. Complete suppression of plasma FGF-2 was observed in 35% of the patients and correlated with clinical response but not OS. Clinical trial information: NCT00049530.

Magnetic resonance spectroscopy as an early indicator of response to anti-angiogenic therapy in patients with recurrent glioblastoma: RTOG 0625/ACRIN 6677

The prognosis for patients with recurrent glioblastoma remains poor. The purpose of this study was to assess the potential role of MR spectroscopy as an early indicator of response to anti-angiogenic therapy. Thirteen patients with recurrent glioblastoma were enrolled in RTOG 0625/ACRIN 6677, a prospective multicenter trial in which bevacizumab was used in combination with either temozolomide or irinotecan. Patients were scanned prior to treatment and at specific timepoints during the treatment regimen. Postcontrast T1-weighted MRI was used to assess 6-month progression-free survival. Spectra from the enhancing tumor and peritumoral regions were defined on the postcontrast T1-weighted images. Changes in the concentration ratios of n-acetylaspartate/creatine (NAA/Cr), choline-containing compounds (Cho)/Cr, and NAA/Cho were quantified in comparison with pretreatment values. NAA/Cho levels increased and Cho/Cr levels decreased within enhancing tumor at 2 weeks relative to pretreatment levels (P = .048 and P = .016, respectively), suggesting a possible antitumor effect of bevacizumab with cytotoxic chemotherapy. Nine of the 13 patients were alive and progression free at 6 months. Analysis of receiver operating characteristic curves for NAA/Cho changes in tumor at 8 weeks revealed higher levels in patients progression free at 6 months (area under the curve = 0.85), suggesting that NAA/Cho is associated with treatment response. Similar results were observed for receiver operating characteristic curve analyses against 1-year survival. In addition, decreased Cho/Cr and increased NAA/Cr and NAA/Cho in tumor periphery at 16 weeks posttreatment were associated with both 6-month progression-free survival and 1-year survival. Changes in NAA and Cho by MR spectroscopy may potentially be useful as imaging biomarkers in assessing response to anti-angiogenic treatment.

Expression of Semaphorin3B protein in human hepatocellular carcinoma and its clinical significance

Objective To investigate the expression of Semaphorin3B (SEMA3B) in hepatocellular carcinoma (HCC) and reveal its clinical significance.Methods Immunohistochemistry and Western blotting were performed to examine the expression of SEMA3B protein in 56 hepatocellular carcinoma samples,matched perineoplastic tissues and 14 normal liver samples.Microvessel density (MVD) was determined by counting CD34-positive endothelial cells.Statistical methods were performed to analyse the relationships between the expression of SEMA3B and clinicopathologic factors.Results The rate of the SEMA3B-positive in HCC tissues was 42.9％ and significantly lower than that in normal liver tissues and non-cancerous adjacent liver tissues(78.6％ and 85.7％,respectively)(P＜0.05).MVD in SEMA3B-positive HCC tissus was lower than that in SEMA3B-negative HCC tissus (P＜0.05).The expression of SEMA3B was closely related to tumor nodular number,tumor size,tumor capsulation and CLIP score (P＜0.05 for all).The recurrence and metastasis rate in SEMA3B-positive group was lower than that in the negative group(P＜0.05),and the survival rate in positive group was higher than that in the negative(P＜0.05).Conclusion The expression of SE-MA3B was decreased in HCC tissues,and its expression was closely associated with tumor progression,angiogenesis and prognosis,indicating that it might seve as a predictor of prognosis and a possible novel target of antiangiogenic therapy for patients with HCC. Key words: Hepatocellular carcinoma; Semaphorin3B; Microvessel density; Recurrence; Prognosis

Unfolded protein response (UPR) signalling in anti-angiogenic therapy for patients with breast cancer resistance to current anti-VEGF agents

Unfolded protein response (UPR) signalling in anti-angiogenic therapy for patients with breast cancer resistance to current anti-VEGF agents

Molecular Biomarkers of Response to Antiangiogenic Therapy for Cancer

Antiangiogenic therapy for cancer has gone from an intriguing hypothesis in the 1970s to an accepted treatment approach for many cancer types. It has also become a standard of care for certain eye diseases. Yet, despite the use of molecularly targeted drugs with well defined targets, to date there are no biomarkers to guide the use of antiangiogenic therapy in patients. The mechanisms of action of these drugs are also being debated. This paper discusses some of the emerging biomarker candidates for this type of cancer therapy, which have provided mechanistic insight and might be useful in the future for optimizing cancer treatment.

Lycorine hydrochloride inhibits metastatic melanoma cell‐dominant vasculogenic mimicry

Melanoma cells actively participate in tumor angiogenesis and vasculogenic mimicry. However, anti-angiogenic therapy in patients with melanoma has not shown a significant survival gain. Thus, new anti-melanoma angiogenic and vasculogenic drugs are highly desired. Using the metastatic melanoma cell line C8161 as a model, we explored melanoma vasculogenic inhibitors and found that lycorine hydrochloride (LH) effectively suppressed C8161 cell-dominant formation of capillary-like tubes in vitro and generation of tumor blood vessels in vivo with low toxicity. Mechanistic studies revealed that LH markedly hindered expression of VE-cadherin in C8161 cells, but did not affect expression of six other important angiogenic and vasculogenic genes. Luciferase assays showed that LH significantly impeded promoter activity of the VE-cadherin gene in a dose-dependent manner. Together, these data suggest that LH inhibits melanoma C8161 cell-dominant vasculogenic mimicry by reducing VE-cadherin gene expression and diminishing cell surface exposure of the protein.

Anti-angiogenic therapy for colorectal cancer: on the way to getting better!

Based on the theory that tumor growth and metastasis depend on vessels to provide oxygen and nutrients, antiangiogenic therapy was thought as a promising approach to cure cancer. Bevacizumab is the first validated angiogenesis inhibitor, when combined with conventional treatments, which can enhance antitumor effects and prolong survival for patients with colorectal cancer. However, recent years, bevacizumab and other angiogenesis inhibitors are more discussed with drug resistance and the diverse test results. Fortunately, antiangiogenic strategy is more than bevacizumab and more than anti-vascular endothelial growth factor. Dozens of compounds that potently inhibit neoplastic blood vessels formation with different mechanisms have been developed, and many of them are being tested clinically for colorectal cancer. This review will numerate the principal antiangiogenic drugs with various mechanisms, recapitulate the information of studying these drugs for colorectal cancer treatment and try to clue better usage of antiangiogenic therapy for patients with colorectal cancer in the future.

Abstract 1375: Contrasting effects of VEGF pathway inhibitors in primary and metastatic disease using perioperative neoadjuvant mouse models

Abstract Recent clinical trial failures with antiangiogenic therapy in patients with early-stage disease have raised the possibility that drug efficacy in preclinical studies, typically involving models of localized primary grown tumors, may not always predict for efficacy in treating metastatic disease, which is the most common cause of mortality in patients. Moreover, depending on disease stage and treatment circumstances, the efficacy of VEGF-pathway inhibitors administered as monotherapies may be offset in certain settings by increased aggressive invasiveness and augmented metastatic potential. Thus, with hundreds of trials underway in neoadjuvant and adjuvant settings to evaluate the efficacy of antiangiogenic therapy in blocking or slowing micrometastatic disease and eventual tumor recurrence, there is an urgent need clarify the utility of such drugs in all stages of tumor progression. Herein we describe a novel preclinical neoadjuvant therapeutic methodology used to compare the effects of short-term VEGF pathway inhibition in highly metastatic human breast, melanoma, and kidney tumor cells grown orthotopically in SCID mice before and after surgical resection. While cytotoxic chemotherapy administered in the maximum tolerated dose could slow tumor growth and lead to a prolongation of survival after resection, similar significant benefits by various VEGF inhibitors in primary tumor inhibition did not consistently translate into significant prevention of recurrent local and distant metastasis after treatment cessation. Furthermore, reductions in primary tumor growth by neutralizing antibodies to VEGF or VEGFR-2 were more predictive of modest survival benefits after tumor resection, compared to the VEGFR tyrosine kinase inhibitor (TKI) sunitinib, which had either no effect or decreased survival compared to control - despite significant reductions in primary tumor growth after neoadjuvant treatment. Potential tumor-independent ‘host’ drug responses could account for this difference as short-term treatment of immunocompromised nu/nu mice prior to intravenous tumor inoculation lead to modest or negligible benefits with VEGF or VEGFR2 antibodies compared to worse outcomes in VEGFR TKI pre-treated animals. Taken together, preclinical neoadjuvant therapy allows for the distinction of ‘anti-primary’ and ‘anti-metastatic’ effects and may serve as a predictive tool to model ongoing clinical trials as well as indicate potential drug combinations which may be used to overcome limitations when such drugs are used as a monotherapy. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1375. doi:1538-7445.AM2012-1375

Management of treatment-associated toxicites of anti-angiogenic therapy in patients with brain tumors.

Anti-angiogenic therapies, including bevacizumab, are being used with increasing frequency in the management of malignant glioma. Common clinically significant toxicities include hypertension and proteinuria, poor wound healing, and the potential for thromboembolic events. Literature related to the use of bevacizumab in malignant glioma, reported toxicities in this patient population, and management of these toxicities was reviewed. Recommendations for assessment and management are provided. Anti-angiogenic therapies will continue to have a role in the treatment of malignant glioma. Further studies of the prevention, assessment, and management of these toxicities are warranted.

Gingival bleeding and jaw bone necrosis in patients with metastatic renal cell carcinoma receiving sunitinib: Report of 2 cases with clinical implications

There is emerging evidence that oral mucositis/stomatitis is a common adverse effect of sunitininb antiangiogenic therapy in patients with metastatic renal cell carcinoma (mRCC). In addition, a case of sunitinib-related jaw osteonecrosis was recently described. We report on 2 patients with mRCC treated with sunitinib. The first patient, a 19-year-old woman, treated with cisplatin and sunitinib, presented with oral pain, malodor, spontaneous and continuous gingival bleeding, and painful necrotic ulcerations clinically resembling necrotizing ulcerative gingivitis (NUG). Suntinib-related stomatitis and bleeding were considered cumulative to NUG symptoms. The second patient, a 64-year-old woman, treated with sunitinib only, complained of mandibular pain. Sunitinib-related jaw osteonecrosis was diagnosed. Gingival bleeding and soft tissue necrosis, as well as jaw osteonecrosis may develop as adverse events of sunitinib use. Antiangiogenic therapies are increasingly used in the treatment of cancers. The presented cases are aimed to alert health care professionals on adverse oral events.

Antiangiogenic Therapy for Patients with Recurrent and Newly Diagnosed Malignant Gliomas

Malignant gliomas have a poor prognosis despite advances in diagnosis and therapy. Although postoperative temozolomide and radiotherapy improve overall survival in glioblastoma patients, most patients experience a recurrence. The prognosis of recurrent malignant gliomas is dismal, and more effective therapeutic strategies are clearly needed. Antiangiogenesis is currently considered an attractive targeting therapy for malignant gliomas due to its important role in tumor growth. Clinical trials using bevacizumab have been performed for recurrent glioblastoma, and these studies have shown promising response rates along with progression-free survival. Based on the encouraging results, bevacizumab was approved by the FDA for the treatment of recurrent glioblastoma. In addition, bevacizumab has shown to be effective for recurrent anaplastic gliomas. Large phase III studies are currently ongoing to demonstrate the efficacy and safety of the addition of bevacizumab to temozolomide and radiotherapy for newly diagnosed glioblastoma. In contrast, several other antiangiogenic drugs have also been used in clinical trials. However, previous studies have not shown whether antiangiogenesis improves the overall survival of malignant gliomas. Specific severe side effects, difficult assessment of response, and lack of rational predictive markers are challenging problems. Further studies are warranted to establish the optimized antiangiogenesis therapy for malignant gliomas.