Bevacizumab-based Chemotherapy Research Articles

Fractionated Stereotactic Radiosurgery in Recurrent Glioblastoma Multiforme: An Effective Method for Salvage Therapy

Optimal salvage treatment of recurrent Glioblastoma Multiforme (GBM) after second-line Bevacizumab-based chemotherapy remains to be established. A group of such patients was treated with fractionated radiosurgery (FSRS) to a total dose of 32 Gy in 4 fractions. The objective of this study was to evaluate and determine the clinical efficacy of this increased dose FSRS as salvage treatment for recurrent GBM.

Preliminary experience of whole-brain radiation therapy (WBRT) in breast cancer patients with brain metastases previously treated with bevacizumab-based chemotherapy

We report our experience of bevacizumab-based chemotherapy (BBCT) followed by whole-brain radiation therapy (WBRT) for breast cancer (BC) patients (pts) with inoperable brain metastases (BM) or who refused surgery. This is a retrospective study of seven metastatic BC pts treated at the Institut Curie with at least one course of BBCT before WBRT, with a delay of ≤ 12 months between the two treatments. Toxicity was scored according to the common terminology criteria for adverse events (v4. 2010). Median age was 56 years (41-65). Median follow-up was 5.9 months (0.4-24.6). The median dose of bevacizumab was 10 mg/kg. Median number of cycles BBCT was six (5-17). Different chemotherapy regimens were used, the most common combination was paclitaxel-bevacizumab. WBRT was delivered in ten fractions, five fractions/week, for two weeks, to a total of 30 Gy. One pt underwent stereotactic radio surgery (SRS) after WBRT. No pt received BBCT during RT. Most common reported side-effects were nausea (n = 4), headache (n = 3), vomiting (n = 1), and vertigo (n = 3). All pts had mild or moderate grade ≤ 2 neurologic toxicity. There were no radiological signs of necrosis or cerebral ischemia. BBCT before WBRT was not associated with severe brain toxicity. Because of the limited number of pts, the different BBCT regimens, and important delays between treatments, these results must be confirmed prospectively.

Does visceral fat area (VFA) have predictive value for hypertension (HTN) and progression-free survival (PFS) in patients (pts) with stage IV NSCLC receiving bevacizumab (Beva)?

e18005 Background: Visceral fat releases pro-angiogenic factors that may promote tumour growth. VFA has been suggested as a predictor of outcome in colorectal and renal cancer pts receiving anti-VEGF agents (Guiu, Gut 2010; Ladoire, Oncologist 2011). Moreover, HTN seems to reflect the intensity of VEGF pathway inhibition, and could also predict outcomes in pts receiving Beva. We postulated that VFA could impact both the activity and toxicity of Beva. Methods: An electronical medical record review identified all pts with stage IV non-squamous NSCLC who received a platinum doublet plus Beva as first-line treatment in our outpatient unit. Beva was continued until disease progression or unacceptable toxicity in pts with response or stable disease after 6 cycles. VFA was determined from pre-treatment CT scans. HTN was monitored at home twice daily according to international guidelines, and graded according to the NCI-CTC v4.0 criteria. Pts were dichotomized according to their VFA (above or below the median), and potential associations linking VFA to HTN, PFS and OS were examined. Results: A total of 77 pts (65% males, 64% smokers, 36% with a PS of 2, median age: 57 years, range 38-86) were eligible for this analysis. Eighteen pts (23%) had a past history of HTN, well controlled at initiation of Beva. A total of 730 cycles of bevacizumab (median/pt: 6, range 2-22) were given. Grade ≥ 2 HTN was observed in 26 (34%) pts. At a median follow-up of 10.1 months (range: 1.0-35.3), the median PFS and OS were 6.9 months (95%CI: 5.6-8.6) and 10.6 months (95%CI: 9.8-11.7), respectively. Median VFA was 113.2 cm2 (range: 27.2-265.2). HTN was significantly more frequent in pts with a low VFA (46% vs. 21 %, OR 3.1, p = 0.03). Patients with a low VFA had a significantly longer PFS: 8.5 (95%CI: 6.4-9.4) vs. 5.6 months (95%CI: 4.8-7.5), p = 0.04. No difference was observed regarding OS. Conclusions: In this series of unselected NSCLC pts receiving bevacizumab-based chemotherapy, pts with a low VFA were more likely to experience HTN and a better PFS than pts with a high VFA. Further studies are required to validate this biomarker in different datasets.

Circulating endothelial cells predict for response to bevacizumab-based chemotherapy in metastatic colorectal cancer

Standardized enumeration of CEC counts is required to minimize variability and allow cross-studies comparisons. The purpose of this paper is to identify CEC threshold proposal, by CellSearch system, for determining response to bevacizumab-based chemotherapy in metastatic colorectal cancer. From July 2007 to June 2008, 33 patients treated with FOLFOX4 plus bevacizumab were enrolled in a prospective study. From January 2007 to June 2007, before bevacizumab was approved by the government in Japan, 31 patients treated with FOLFOX4 as a control were enrolled. CECs of whole blood at the baseline, day 4, 2weeks after initiation of chemotherapy were isolated and counted using CellSearch system. There was no correlation between CEC levels and the outcome in the FOLFOX4. In the bevacizumab-based chemotherapy, CEC levels at the baseline were significantly associated with the outcome. Patients with 65 or more CECs at the baseline had a shorter median PFS and OS, than the median PFS and OS of less than 65 CECs at the baseline in the bevacizumab-based chemotherapy (P=0.003, P=0.027, respectively). By univariate and multivariate Cox proportional-hazards regression, CEC levels (cut-off; 65) at the baseline indicated the strongest predictor for the outcome to bevacizumab-based chemotherapy. A threshold of lower than 65 CECs, by the CellSearch System, at the baseline was a significant predictor of the outcome for colorectal cancer patients treated with bevacizumab-based chemotherapy.

The effect of bevacizumab on serum soluble FAS/FASL and TRAIL and its receptors (DR4 and DR5) in metastatic colorectal cancer

Bevacizumab-based chemotherapy has become the standard of care in metastatic colorectal cancer (MCRC). We aimed to measure the levels of serum soluble FAS, FASL, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), and its death receptors DR4 and DR5 in MCRC patients and to define prognostic significance of these parameters in response to bevacizumab in these patients. The levels of these parameters in serum samples were quantified by a commercially available ELISA kit in 31 MCRC patients before and after 2 cycles of therapy and 25 healthy controls. Pretreatment sFAS levels in MCRC patients was significantly lower than the levels of controls (p = 0.043). There was no significant difference in sFAS and sFASL levels in MCRC patients before and after bevacizumab-based treatment. There was no significant difference in sFAS/sFASL ratio in MCRC patients before and after treatment and controls. Soluble DR5 levels were significantly higher in pretreatment serum samples compared with controls (p = 0.008). However, pretreatment sTRAIL and sDR4 levels were similar to the levels of controls. There was no significant difference in sTRAIL, sDR4, and sDR5 levels in MCRC patients before and after treatment. When patients were grouped according to treatment response (responders vs. non-responders), post-treatment sFAS/sFASL ratio was significantly lower in responding patients compared with non-responders (p = 0.029). Significant correlations were observed between post-treatment sFASL and sDR4, sFAS and sTRAIL, sTRAIL and sFAS/sFASL ratio, and sFASL and sDR5. Non-significant changes in apoptotic markers with bevacizumab-based chemotherapy showed that they have no prognostic significance in MCRC patients. Significant change in sFAS/sFASL ratio according to treatment response could be an indicator of chemosensitivity.

Thromboembolic Events in Patients With Colorectal Cancer Receiving the Combination of Bevacizumab-Based Chemotherapy and Erythropoietin Stimulating Agents

To investigate whether the incidence of thromboembolic events (venous and arterial) increases when bevacizumab-based chemotherapy and erythropoietin stimulating agents (ESAs) are used in combination versus alone. A retrospective, pilot study of 79 colorectal cancer patients treated with chemotherapy were divided into 3 groups: bevacizumab (n = 28), ESA (n = 21), and bevacizumab plus ESA (n = 28). The primary end point was the incidence of thromboembolic events. Secondary endpoints included median time-to-event; effect of anticoagulation; and association with concurrent chemotherapy, baseline risk factors, hemoglobin, and performance status. The incidence of thromboembolic events was 11% in the bevacizumab group, 23.8% in the ESA group, and 30% in the combination group (P = 0.194). The median time-to-event was 7.5, 3.5, and 2.5 months, respectively (P = 0.060). The 5 month difference in time-to-event between the bevacizumab group and combination group was significant (P = 0.045). When combining all patients, ESA treatment, prior venous thromboembolic event (VTE), obesity, cardiac disease, and use of exogenous hormones were strong predictors for thromboembolic events. Prior VTE was a strong predictor in those patients in the combination group. The incidence of thromboembolic events was increased with the combination of bevacizumab plus ESA compared with either agent alone with chemotherapy. Median time-to-event in the combination group was significantly shorter compared with the bevacizumab group. Prior VTE, cardiac disease, obesity, and exogenous hormone use should be taken in consideration when using the combination of bevacizumab and ESAs.

A bowel perforation with metallic stent placement for advanced rectal cancer during bevacizumab-based chemotherapy

A bowel perforation with metallic stent placement for advanced rectal cancer during bevacizumab-based chemotherapy

Predictive Value of Circulating Tumor Cells (CTCs) in Metastatic Breast Cancer Patients Treated by Bevacizumab-Based Therapy.

Abstract Background:Circulating tumor cells (CTC) are involved in cancer dissemination and are an independent prognostic factor in metastatic breast cancer (MBC). Antiangiogenic, bevacizumab-based chemotherapy improves response rate and progression free survival in patients with metastatic breast cancer (MBC), without impact on overall survival. Preclinical data suggest the possibility of increased metastatic potential of tumor cells pretreated by anti-angiogenic therapy (Ebos et al. Cancer Cell 2009,15: 232–9). The aim of this study was to determine the prognostic value of CTC in MBC patients treated by bevacizumab-based therapy.Patients and Methods: This retrospective study included 48 MBC treated with bevacizumab combined chemotherapy regimens and 46 patients treated with chemotherapy alone between January 2004 and December 2008 at M.D.Anderson Cancer Center. CTCs were detected and enumerated before patients started therapy using the CellSearch™ system (Veridex, LLC, NJ, USA). Progression free survival (PFS) and overall survival (OS) were calculated from the date of CTC measurement, estimated by the Kaplan-Meier product limit method, and compared between groups with the log-rank test.Results: At a median follow up of 10.1 months (range: 1-26 months), 22 patients (45.8%) had died. The estimated medians of PFS in bevacizumab-treated patients were 8.1 vs. 5.2 months (p = 0.42) in patients with baseline < 5 CTCs vs. ≥ 5 CTCs. Moreover, the OS for the two subgroups were 18.3 vs. 12.4 months (p = 0.41), respectively. Twenty-three patients had CTC measurements at the time of progression. Median CTC counts at baseline and at time of disease progression were 6 (range: 0-230) and 7 (range: 0-359) respectively in the bevacizumab-treated group. The median CTC counts in the control group at same time points were 7 (range: 0-724) and 2 (range:0-999), respectively. Thirteen (56.5%) and 12 (52.2%) patients had CTC ≥ 5 at baseline and at time of disease progression in bevacizumab-treated group compared to CTC counts of 24 (52.2%) and 17 (37%) in control group treated with chemotherapy without bevacizumab. Post progression overall survival in patients with CTC < 5 and CTC ≥ 5 measured at time of disease progression were 11.0 and 10.4 months (p = 0.36), in the bevacizumab treated group vs. 27 and 12.4 months (p = 0.04), in the control group respectively.Conclusion: Our data support the prognostic value of CTC measured before therapy in MBC. The detection of higher CTC counts at time of disease progression and the limited prognostic value of CTC after failure of bevacizumab-based chemotherapy although intriguing, warrants further prospective investigations. Moreover, a comparison between the differential effects of monoclonal antibodies and tyrosine kinases inhibitors on CTCs detection and monitoring will better clarify the role of specific targeted therapies on micrometastatic disease. Citation Information: Cancer Res 2009;69(24 Suppl):Abstract nr 3013.

Carbonic anhydrase 9 is a predictive marker of survival benefit from lower dose of bevacizumab in patients with previously treated metastatic colorectal cancer

BackgroundCarbonic anhydrase 9 (CA9) is a marker for hypoxia and acidosis, which is linked to a poor prognosis in human tumors. The purpose of this comparative analysis was to evaluate whether CA9 and VEGF expression are associated with survival outcomes in patients with metastatic colorectal cancer (mCRC) after treatment with bevacizumab as second or later line treatment.MethodsThirty-one mCRC patients who were treated with bevacizumab-containing chemotherapy as second or later line treatment and who had analyzable tumor paraffin blocks were selected for this study. The planned dose of bevacizumab was 5 mg/kg/2-week. Immunohistochemical (IHC) staining of CA9 and VEGF was performed and their expression was scored by the intensity multiplied by percentage of stained area.ResultsThe overall response rate was 19.4% and the disease control rate (DCR) was 61.3% with 6 partial responses and 13 cases of stable disease. The DCR was significantly higher in patients with a lower CA9 expression score compared to those with a higher score (80.0% vs. 27.3%, respectively, P = 0.004). The patients with a low CA9 expression score also showed better outcomes with regard to the median progression-free survival (P = 0.028) and overall survival (P = 0.026). However, VEGF expression was not associated with the DCR and survival.ConclusionLower degree of CA9 expression was associated with better clinical outcomes in patients with mCRC treated with lower dose bevacizumab-based chemotherapy. Prospective studies are now needed to determine the correlation between CA9 expression and clinical outcomes after bevacizumab treatment, at different doses and in varied settings.

Polymorphisms and Clinical Outcome in Recurrent Ovarian Cancer Treated with Cyclophosphamide and Bevacizumab

This study was designed to evaluate the associations between angiogenesis gene polymorphisms and clinical outcome in ovarian cancer patients treated with low-dose cyclophosphamide and bevacizumab. Seventy recurrent/metastatic epithelial ovarian cancer patients were enrolled in a phase II clinical trial. Genomic DNA was available from 53 blood samples. Polymorphisms were analyzed using the PCR-RFLP protocol. A 5' end 33P gammaATP-labeled PCR protocol was used to analyze dinucleotide repeats. Patients genotyped A/A or A/T for the IL-8 T-251A gene polymorphism had a statistically significant lower response rate (19%; 0%) than those homozygous T/T (50%; P = 0.006, Fisher's exact test). Patients carrying a minimum one C allele (C/C; C/T) of the CXCR2 C+785T polymorphism showed a median progression-free survival (PFS) of 7.4 months compared with the PFS of 3.7 months for those homozygous T/T (P = 0.026, log-rank test). Patients with the VEGF C+936T polymorphism C/T genotype had a longer median PFS of 11.8 months, compared with those with the C/C and T/T genotype, which had median PFS of 5.5 months and 3.2 months, respectively (P = 0.061, log-rank test). Patients carrying both AM 3'end alleles < 14 CA repeats had the shortest median PFS of 3.4 months; patients with at least one allele > 14 repeats or both alleles > 14 repeats showed a median PFS of 6.4 months and 7.2 months, respectively (P = 0.008, log-rank test). Our data suggest that the IL-8 A-251T polymorphism may be a molecular predictor of response to bevacizumab-based chemotherapy. The CXCR2 C+785T, VEGF C+936T single nucleotide polymorphisms and the AM 3' dinucleotide repeat polymorphisms may be molecular markers for PFS in ovarian cancer patients.

Hepatic metastases (HM) from colorectal cancer (CRC): Resectability and survival after treatment with oxapliplatin or irinotecan + bevacizumab-based chemotherapy

15091 Background: In the last decade, CCR treatment has suffered great changes with the introduction of new agents, mainly since Bevacizumab approval by FDA as first line treatment. Treatment of he...

Alterations in serum prothrombotic markers induced by treatment with bevacizumab-based chemotherapy regimens

15034 Background: An increase in thrombotic events has been observed during treatment with chemotherapy and bevacizumab in patients with metastatic carcinoma. A better understanding of the effect of bevacizumab on haemostasis is necessary to determine the true thrombogenic potential of this drug. Methods: 10 patients with metastatic colorectal cancer (mCRC) commencing first line or salvage chemotherapy with bevacizumab were included in this prospective trial. Plasma samples were drawn at baseline, after the first cycle of treatment containing chemotherapy alone and after the second cycle containing chemotherapy plus bevacizumab. The study evaluated alterations of markers of procoagulant activation, natural anticoagulants, endothelial cell and platelet activation. The markers analysed were: prothrombin time (PT), activated partial thromboplastin (aPTT), D-Dimer (D-Di), fibrinogen (Fibn), factor VIII (FVIII), activated protein C (APCR), protein C (PC), free protein S (fPS), soluble P-selectin (sP-sel), platelet count (plt), von Willebrand factor antigen (vWF:ag) and von Willebrand factor activity (vWF:act). Results: The mean basal levels of D-Di and Fibn were increased above the normal range and remained elevated throughout the course of treatment analysed. Significant differences were noted in the levels of PC, plt and vWF:ag between the basal values and post-cycle 2 results (p=0.003, p=0.007 and p=0.05 respectively). The mean pre-treatment and post-chemotherapy cycle 1 levels of sP-sel were also above the normal range but were in the normal range after the second cycle. A thrombotic event occurred in one patient after the second cycle of chemotherapy. Conclusion: Metastatic CRC is associated with a prothrombotic state. A reduction in natural anticoagulation (PC) and increased vascular activation (vWF:ag) was seen in patients treated with bevacizumab. Platelet activation, as demonstrated by P-selectin levels was reduced with chemotherapy and normalised with the addition of bevacizumab. These data not only support prior observations of the prothrombotic state in cancer patients treated with chemotherapy, but also provides in vivo evidence of the mechanisms of the procoagulant effect of bevacizumab-based chemotherapy. No significant financial relationships to disclose.

Complications and effectiveness of combination chemotherapy in metastatic colorectal cancer (MCRC) with unresected primary (UP)

14537 Background: The outcome of patients (pts) with MCRC and unresected primary (UP) has not been studied systematically in the modern era of targeted and combination chemotherapy. We conducted a single institute retrospective study to determine the rate and nature of complications in this population. Methods: MCRC-UP pts treated at Roswell Park Cancer Institute between 2002 and 2006 were identified. Demographic, toxicity, efficacy, and palliative intervention data were collected. Primary tumor related complications including obstructive symptoms, bleeding, perforation, and fistulas were assessed. Results: 24 pts with colonic UP were identified. 14/24 were treated with bevacizumab-based chemotherapy (11 FOLFOX, 3 capecitabine), 7/24 with FOLFOX, 2 with capecitabine, and 1 with FOLFIRI. No perforations, hemorrhagic events, or arterial events were noted. None of the 24 pts required palliative surgical intervention secondary to the UP. Only 2 pts developed obstructive symptoms and 1 pt developed an entero-cutaneous fistula; all 3 events were attributed to peritoneal carcinomatosis. 10 pts with rectal UP were identified. 1 pt received upfront chemoradiation followed by 5-FU/bevacizumab. 9/10 pts were treated with upfront systemic chemotherapy (6 bevacizumab-based [5 FOLFOX, 1 capecitabine], 3 FOLFOX). Of these 9 pts, 4 required subsequent palliative radiation therapy for obstructive symptoms (3 pts) or pain (1pt) while 5 continue on systemic chemotherapy (median 1st line chemotherapy duration &gt; 7 months). No perforations, bleeding requiring transfusion, or arterial events were noted among the rectal cancer population. 1 pt required a diverting colostomy for obstruction despite palliative CRT. Median time to progression on first line chemotherapy was 7.4 months for colon cancer and 8 months for rectal cancer. The median overall survival was 13.6 months for colon cancer and has not been reached for rectal cancer (exceeded 13 months). Conclusion: Treatment of MCRC with UP is feasible and is rarely associated with complications related to the primary tumor. Rectal cancer with UP can be managed with upfront chemotherapy. Subsequent palliative RT is needed in about 50% of these pts. No significant financial relationships to disclose.

Angiogenesis pathway gene polymorphisms associated with clinical outcome in recurrent ovarian cancer treated with low dose cyclophosphamide and bevacizumab: A California Consortium Trial

5017 Background: Despite advances in chemotherapy, ovarian cancer remains a major cause of cancer mortality worldwide. It has therefore become essential to identify novel therapeutic targets, such as angiogenesis which is a complex process regulated by the delicate balance between various local proangiogenic and antiangiogenic proteins. Bevacizumab, a monoclonal antibody binding to VEGF, has shown significant activity in colon, breast, lung and ovarian cancer. There are no established molecular markers to predict response or time to tumor progression for Bevacizumab based chemotherapy. The key enzymes of the VEGF pathway are: Vascular Endothelial Growth Factor (VEGF), VEGF Receptor (VEGFR), Hypoxia Inducible Factor1 (HIF α and β-subunit), Neuropilin1 (NRP), Interleukin-8 (IL-8), Adrenomedullin (AM) and Leptin. Methods: Seventy patients with refractory ovarian cancer were enrolled in a Phase II clinical trial and treated with Cyclophoshamide 50 mg po/Bevacizumab 10 mg/kg IV every 14 days. From 52 patients blood samples were available for gDNA extraction and PCR-RFLP assays. Results: 13 patients had a PR (25%) and 39 were non responders. 31 pts had progressed. Median follow-up of 8.3 months with a median progression-free survival of 6.6 months. Patients who were homozygous A/A or heterozygous A/T genotype at the −251 locus in the IL-8 gene had a lower response rate than those who were T/T (P = 0.047 Fisher’s exact test). Patients with Vegf936 C/C had a median TTP of 6.5 months, pts with any T (T/T, C/T) had a median TTP of 17.2 months. Pts carrying both AM 3’end alleles &lt;14 CA repeats had 3.4 months median TTP, patients with at least one allele &gt;14 showed a median TTP of 6.6 months; for both alleles &gt;14 patients showed 8.7 months of median TPP (P = 0.0006 Log-rank test) Conclusions: Our data suggest for the first time, that IL-8 may be a potential molecular predictor of response to Bevacizumab based chemotherapy. We also demonstrate that both VEGF 936 and the AM 3’ dinucleotide repeat polymorphisms are potential molecular markers for time to tumor progression. A larger prospective study is needed to validate and confirm our preliminary findings. This study was supported by NCI grant NO1 CM 17101. [Table: see text]