Bevacizumab-containing Chemotherapy Research Articles

Pathological complete response after neoadjuvant chemotherapy for rectal cancer with synchronous multiple liver metastases: a report of an unusual case.

BackgroundSystemic chemotherapy for stage IV colorectal cancer has advanced markedly in the recent years. We report an unusual case of 13 synchronous liver metastases for which a pathological complete response was achieved with neoadjuvant chemotherapy (NAC) consisting of a combination of 5-fluorouracil (5-FU), oxaliplatin, leucovorin (mFOLFOX6), and bevacizumab.Case presentationA 44-year-old man was diagnosed with colorectal cancer with synchronous liver metastases. We resected the primary rectal tumor first. Further, after providing NAC for hepatic metastases, lateral segmentectomy and partial resection of the liver were performed. The subsequent result was compatible with a complete pathological response. The postoperative course was uneventful, and the patient is currently alive 5 years after the first surgery without evidence of recurrence and without adjuvant chemotherapy.ConclusionsFor patients with initially resectable colorectal liver metastases, the survival benefits of NAC are still unclear. We report a rare case of 13 synchronous liver metastatic lesions from rectal cancer with a complete pathological response after neoadjuvant bevacizumab-containing chemotherapy.

High serum levels of interleukin-6 in patients with advanced or metastatic colorectal cancer: the effect on the outcome and the response to chemotherapy plus bevacizumab.

We evaluated the relationship of the pretreatment serum IL-6 levels with the outcome and treatment response in patients with advanced or metastatic colorectal cancer (CRC) who underwent bevacizumab-containing chemotherapy. In this retrospective study, the pretreatment serum IL-6 and plasma vascular endothelial growth factor (VEGF) levels were measured in 113 patients with metastatic CRC. The cut-off values for these measurements, as determined by a receiver operating characteristic curve analysis, were 4.3 and 66pg/mL, respectively. The median follow-up period was 19months (range 1-40months). Sixty-three patients had primary cancer, and 38 had a metachronous recurrence. Thirty patients underwent curative resection, and 71 underwent chemotherapy, 53 of whom received bevacizumab-containing chemotherapy. Overall survival (OS) and progression-free survival (PFS) were estimated using Kaplan-Meier and multivariate Cox proportional hazards regression analyses. The plasma VEGF levels and positive KRAS mutation status were not associated with the outcomes. However, high serum IL-6 levels were significantly associated with poorer OS and PFS in comparison to low serum IL-6 levels. A Cox proportional hazards regression analysis showed that high serum IL-6 levels were an independent risk factor for a poor outcome. In patients with metastatic CRC, high pretreatment serum IL-6 levels were associated with a poor outcome and bevacizumab resistance.

Progress on clinical application of bevacizumab for the treatment of refractory cervical cancer

Bevacizumab is increasingly used in recurrent, persistent or metastatic cervical cancer. The early retrospective case reports found that bevacizumab combined with 5-FU (including capecitabine) or paclitaxel was well tolerated and displayed encouraging anti-tumor activity in recurrent or persistent cervical cancer. Phase Ⅱ clinical trials showed that bevacizumab was well tolerated and active in the second- and third-line treatment of patients with recurrent cervical cancer. Large scale phase Ⅱ and phase Ⅲ clinical trials demonstrated that bevacizumab-containing chemotherapy was effective in the first- and second-line treatment of patients with persistent cervical cancer, prolonged survival time and improved remission rate. The article also reviews the research progress on predictive factors of bevacizumab efficacy, showing the use of imaging and biomarkers in predicting the efficacy of bevacizumab treatment. In addition, this article analyzes the cost-effectiveness of bevacizumab, finding that bevacizumab combined with chemotherapy meets the standard of cost-effectiveness.

Bevacizumab plus chemotherapy in elderly patients with previously untreated metastatic colorectal cancer: single center experience.

BackgroundMetastatic colorectal cancer (mCRC) is mainly a disease of elderly, however, geriatric population is underrepresented in clinical trials. Patient registries represent a tool to assess and follow treatment outcomes in this patient population. The aim of the study was with the help of the patients’ register to determine the safety and efficacy of bevacizumab plus chemotherapy in elderly patients who had previously untreated metastatic colorectal cancer.Patients and methodsThe registry of patients with mCRC was designed to prospectively evaluate the safety and efficacy of bevacizumab-containing chemotherapy as well as selection of patients in routine clinical practice. Patient baseline clinical characteristics, pre-specified bevacizumab-related adverse events, and efficacy data were collected, evaluated and compared according to the age categories.ResultsBetween January 2008 and December 2010, 210 patients with mCRC (median age 63, male 61.4%) started bevacizumab-containing therapy in the 1st line setting. Majority of the 210 patients received irinotecan-based chemotherapy (68%) as 1st line treatment and 105 patients (50%) received bevacizumab maintenance therapy. Elderly (≥ 70 years) patients presented 22.9% of all patients and they had worse performance status (PS 1/2, 62.4%) than patients in < 70 years group (PS 1/2, 35.8%). Difference in disease control rate was mainly due to inability to assess response in elderly group (64.6% in elderly and 77.8% in < 70 years group, p = 0.066). The median progression free survival was 10.2 (95% CI, 6.7–16.2) and 11.3 (95% CI, 10.2–12.6) months in elderly and < 70 years group, respectively (p = 0.58). The median overall survival was 18.5 (95% CI, 12.4–28.9) and 27.4 (95% CI, 22.7–31.9) months for elderly and < 70 years group, respectively (p = 0.03). Three-year survival rate was 26% and 37.6% in elderly vs. < 70 years group (p = 0.03). Overall rates of bevacizumab-related adverse events were similar in both groups: proteinuria 21/22 %, hypertension 25/19 %, haemorrhage 2/4 % and thromboembolic events 10/6 %, for elderly and < 70 years group, respectively.ConclusionsIn routine clinical practice, the combination of bevacizumab and chemotherapy is effective and well-tolerated regimen in elderly patients with metastatic colorectal cancer.

Pemetrexed Maintenance Therapy Following Bevacizumab-Containing First-Line Chemotherapy in Advanced Malignant Pleural Mesothelioma

Malignant pleural mesothelioma (MPM) is a lethal disease with poor prognosis. The combination of cisplatin and pemetrexed has been confirmed as the standard of care for nonoperable MPM. Data have shown that the adoption of pemetrexed maintenance therapy (PMT) following first-line treatment appears extremely promising.We describe a 57-year-old man diagnosed as advanced MPM. We treated this patient with PMT after first-line cisplatin-based bevacizumab-containing chemotherapy and residual tumor disappeared after 6 course of PMT. A perfect response and a long progression-free survival (PFS) were reached with tumor mass disappearing and 14 months duration of PFS.This case suggests that adding bevacizumab to standard first-line chemotherapy is feasible and that PMT could be promising and useful for treating advanced MPM. We further entail a review of the literature on the first-line treatment, continuation maintenance therapy, switch maintenance therapy, and second-line treatment of patients with advanced MPM.

Perirenal hematoma in a patient treated with bevacizumab for metastatic colon cancer: A case report.

The present study reports the case of a patient that developed spontaneous perirenal hematoma during treatment with bevacizumab-containing chemotherapy. A 44-year-old woman with metastatic sigmoid colon cancer, who was being treated with bevacizumab (5 mg/kg, intravenous, 90 min biweekly), was admitted to hospital following 3 cycles of chemotherapy, with a sudden onset of dyspnea and oliguria. An emergency hemodialysis was performed and a large right perirenal hematoma was diagnosed using computed tomography. The patient was immediately instructed to discontinue chemotherapy, including bevacizumab. However, the right perirenal hematoma increased in size and a left perirenal hematoma developed 3 weeks later. The two perirenal hematomas stabilized 7 weeks subsequent to the termination of bevacizumab treatment. Spontaneous perirenal hematoma due to bevacizumab treatment is an extremely rare occurrence. However, physicians should be aware of this potential complication associated with bevacizumab treatment.

FIRST LINE 5-FU-BASED CHEMOTHERAPY WITH/WITHOUT BEVACIZUMAB FOR METASTATIC COLORECTAL CANCER: TISSUE BIOMARKER CANDIDATES

Purpose: Colorectal cancer is the second leading cause of cancer mortality in the USA. According to Bulgarian National Statistics Institute, 2370 colon and 1664 rectal cancer cases were diagnosed in 2012 with total number of patients 29995. Adding bevacizumab to chemotherapy in patients with metastatic disease improves progression-free survival (PFS) but no predictive markers have been proven in the clinical practice. In our study we examined two tissue biomarkers that may correlate with response to bevacizumab-containing chemotherapy in patients with metastatic colorectal cancer. Patients and Methods: 54 patients with metastatic colorectal cancer were assigned to first line 5-Fu-based chemotherapy with/without bevacizumab. The primary end point was PFS, with additional determination of response and toxicity. Paraffin-embedded samples from primary tumors were collected from all 54 patients. Expression levels of two tumor biomarkers VEGFR-2 and Neuropilin 1 (NP1) were evaluated with immunohistochemistry. Results: The median PFS for the group treated with CT/Bev was 8.8 months, compared with 5.4 months for the group with chemotherapy alone (95% CI, log-rank test P =0.003). The corresponding overall response rates were 19.3% and 10.2% respectively (P < 0.05 for CT/Bev vs CT). Patients with low NP-1 had statistically significant prolongation of PFS as compared to those with high NP-1 (95% CI, log rank test p= 0.017). Patients with low NP-1 appeared to experience a larger bevacizumab treatment effect in terms of PFS (p=0,049,HR 0.333, 95% CI, 0.111 to 0.995) than patients with high NP-1. Conclusion: The addition of bevacizumab to 5-Fu based chemotherapy improves PFS for patients with metastatic colorectal cancer. Expression of tumor NP-1 is a potential biomarker candidate for prediction of clinical outcome in patients with metastatic colorectal cancer, treated with first line chemotherapy plus bevacizumab.

Pemetrexed and bevacizumab-containing chemotherapy for pleomorphic carcinoma of the lung.

Pleomorphic carcinoma of the lung is a rare, highly malignant subtype of lung cancer, with a more aggressive clinical course compared with other types of non-small-cell lung cancer (NSCLC). Pemetrexed and bevacizumab are currently evaluated as two of the most reliable chemotherapeutic drugs for advanced NSCLC. We herein report a case of a 68- and a 46-year-old man with recurrent and chemo-naïve pleomorphic carcinoma of the lung, respectively, who were treated with a combination of carboplatin, pemetrexed and bevacizumab. The overall survival after the initiation of chemotherapy was 30 and 8 months, respectively. These cases exhibited a relatively long-term survival with chemotherapy. In the absence of definitive clinical trials, which are unlikely to be performed due to the rarity of this tumor, our cases demonstrated the potential utility of pemetrexed- and bevacizumab-containing chemotherapy. Our results also suggested that pemetrexed-containing chemotherapy may be key to the treatment of pleomorphic carcinoma of the lung.

Placenta growth factor and neuropilin-1 collaborate in promoting melanoma aggressiveness.

The placenta growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family, which shares with VEGF-A the tyrosine kinase receptor VEGFR-1 and the co-receptor neuropilin-1 (NRP-1). In melanoma models, PlGF enhances tumour growth and neovessel formation, whereas NRP-1 promotes the metastatic process. Increased secretion of PlGF and expression of NRP-1 have also been involved in intrinsic or acquired resistance to anti‑angiogenic therapies. In this study we investigated whether PlGF and NRP-1 cooperate in promoting melanoma aggressiveness independently of VEGFR-1. For this purpose, the melanoma cell clones M14-N, expressing NRP-1 and lacking VEGFR-1, and M14-C, devoid of both receptors, were used. M14-N cells are characterized by an invasive phenotype and vasculogenic mimicry, whereas M14-C cells possess a negligible invasive capacity. The results indicated that M14-N cells secrete higher levels of PlGF than M14-C cells and that PlGF is involved in the invasion of the extracellular matrix (ECM) and vasculogenic mimicry of M14-N cells. In fact, neutralizing antibodies against PlGF reverted ECM invasion in response to PlGF and markedly reduced the formation of tubule-like structures. Moreover, M14-N cells migrated in response to PlGF and chemotaxis was specifically abrogated by anti-NRP-1 antibodies, demonstrating that PlGF directly activates NRP-1 in the absence of VEGFR-1. We also compared the levels of PlGF in the plasma of patients affected by metastatic melanoma with those of healthy donors and evaluated whether PlGF levels could be affected by a bevacizumab-containing chemotherapy regimen. Melanoma patients showed a 20-fold increase in plasma PlGF and the bevacizumab-containing regimen induced a reduction of VEGF-A and in a further increase of PlGF. In conclusion, our studies suggest that the activation of NRP-1 by PlGF directly contributes to melanoma aggressiveness and represents a potential compensatory pro-angiogenic mechanism that may contribute to the resistance to therapies targeting VEGF-A.

Primary Tumour Resection Could Improve the Survival of Unresectable Metastatic Colorectal Cancer Patients Receiving Bevacizumab-Containing Chemotherapy

Background: The effect of primary tumour resection (PTR) among metastatic colorectal cancer (mCRC) patients remains controversial. Combination chemotherapy with bevacizumab could improve the clinical outcomes of these patients, which might change the importance of PTR in the multi-disciplinary treatment pattern. Methods: We performed a non-randomized prospective controlled study of mCRC pts whose performance status (PS) scored ≤2 and who received bevacizumab combination chemotherapy (FOLFOX/XELOX/FOLFIRI) as a first-line therapy. These patients were classified into the PTR group and the IPT (intact primary tumour) group according to whether they underwent PTR before receiving the systemic therapy. The progression free survival (PFS) time and overall survival (OS) time, which were recorded from the start of the primary diagnosis until disease progression and death or last follow-up, were analysed. We also compared severe clinical events (such as emergency surgery, radiation therapy, and stent plantation) between the two groups. Results: One hundred and nighty-one mCRC pts (108 male patients and 93 female patients) were entered in this prospective observational study. The median age was 57.5 years old. The clinical characteristics (age, gender, performance status, primary tumour site, RAS status, and the number of metastatic organs) did not significantly differ between the two groups. The median PFS and OS times of the PTR group were superior than those of the IPT group (10.0 vs 7.8 months, p < 0.01 and 22.5 vs 17.8 months, p < 0.01, respectively). The incidences of adverse events associated with systemic therapy were similar between the two groups. Specifically, sixteen patients (21.9%, 16/73) with IPT developed significant primary tumour-related complications, such as bleeding, obstruction or even perforation. Among these patients, five underwent emergency surgery, three patients received a stent, and eight patients underwent radiation therapy. Conclusions: The mCRC patients who received PTR and bevacizumab combination chemotherapy had better clinical outcomes than patients who did not receive PTR. PTR also decreased the incidence of severe clinical events and improved quality of life.

Bevacizumab in Combination with Chemotherapy for Colorectal Brain Metastasis

Brain metastases are rare in patients with colorectal cancer, but the incidence is expected to rise due to prolonged survival resulting from more effective regimens including anti-EGF-receptor and anti-angiogenic antibodies. Because of the potential fear of intracranial hemorrhage, patients with colorectal brain metastases have been excluded from clinical trials involving bevacizumab or aflibercept. Five patients with colorectal brain metastases treated with bevacizumab-containing chemotherapy regimen following either neurosurgery, radiosurgery, or whole-brain radiotherapy were identified between 2009 and 2014. The clinicopathological data and outcomes for these patients were reviewed. Mean time to disease progression concerning brain metastases was 14.8 months (range 5-25). Overall survival was 26.2 months (range 7-42 months) and overall survival since diagnosis of brain metastases was 20.6 month (7-42). Best response was a partial response in two and a stable disease in three patients. Treatment-related adverse events were mild hypertension (grade 1), diarrhea (grade 1), and fatigue (grade 1). No intracranial hemorrhage was observed. Bevacizumab in combination with chemotherapy is a feasible option for palliative treatment of patients with colorectal brain metastasis with a good safety profile.

Variations in genes regulating tumor-associated macrophages (TAMs) to predict outcomes of bevacizumab-based treatment in patients with metastatic colorectal cancer: results from TRIBE and FIRE3 trials

Tumor-associated macrophages (TAMs) with the M2-like phenotype are regulated by mainly NF-kB pathway including TBK1, which can influence tumor progression by secretion of proangiogenic factors such as vascular endothelial growth factor. The CCL2/CCR2 axis, histidine-rich glycoprotein (HRG), and placenta growth factor (PIGF) play a critical role in the polarization of M1/M2 phenotypes and the recruitment of TAMs to tumor microenvironment. We therefore hypothesized that variations in genes involved in regulating TAMs may predict clinical outcomes of bevacizumab treatment in patients with metastatic colorectal cancer (mCRC). We analyzed genomic DNA extracted from samples of patients receiving bevacizumab plus FOLFIRI as a first-line treatment using PCR-based direct sequencing. Twelve functional single-nucleotide polymorphisms in eight genes (CCL2, CCR2, HRG, PIGF, NFKB1, TBK1, CCL18, and IRF3) were tested for associations with clinical outcomes in a discovery cohort of 228 participants in TRIBE trial (NCT00719797), then validated in 248 KRAS exon2 (KRAS) wild-type participants in FIRE3 trial (NCT00433927). FIRE3-cetuximab cohort served as a negative control. TBK1 rs7486100 was significantly associated with overall survival in 95 KRAS wild-type patients of TRIBE cohort in univariate analysis and had a strong trend in multivariable analysis; furthermore, the association of the T allele was observed for progression-free survival (PFS) in both univariate and multivariable analyses in FIRE3-bevacizumab but not cetuximab cohort. CCL2 rs4586, CCL18 rs14304, and IRF3 rs2304205 had univariate and multivariable correlations with PFS in KRAS mutant patients of the TRIBE cohort, whereas they had no correlations in KRAS wild-type patients of the TRIBE cohort. No association was seen in control cohort. Our study demonstrates for the first time that variations in genes regulating TAMs-related functions are significantly associated with clinical outcomes in mCRC patients treated with bevacizumab-containing chemotherapy. These results also suggest that some TAM-related gene variations may predict outcomes of bevacizumab treatment in KRAS status-dependent manner.

Treatment of choroid metastasis from lung adenocarcinoma with bevacizumab-containing chemotherapy: A case report.

The occurrence of ocular metastasis from lung cancer is uncommon. The present study reports the case of a 69-year-old female patient with lung adenocarcinoma who was found to have a metastatic lesion in the left choroid at the time of presentation. As the patient was found to have a mutation in the epidermal growth factor receptor, treatment with gefitinib was administered; however, the response was evaluated as a progressive disease. Thereafter, the patient received chemotherapy with carboplatin, pemetrexed and bevacizumab. Radiological imaging revealed shrinkage of the primary lesion and choroidal metastasis, and the visual power of the left eye was also shown to improve. Therefore, the present case report demonstrated the efficacy and safety of systemic bevacizumab therapy in combination with a platinum doublet for the treatment of choroid metastasis, with morphological and functional improvements observed with regard to the choroidal metastatic tumor.

Angiogenesis inhibitors rechallenge in patients with advanced non-small-cell lung cancer: a pooled analysis of randomized controlled trials.

PurposeData on the role of angiogenesis inhibitors (AIs) rechallenge in the treatment of advanced non-small-cell lung cancer (NSCLC) patients who previously received bevacizumab remain limited. We aim to investigate the efficacy of AIs in the treatment of advanced NSCLC in this setting.MethodsStudies from PubMed, Web of Science, and abstracts presented at American Society of Clinical Oncology meeting up to December 1, 2014 were searched to identify relevant studies. Eligible studies included prospective randomized controlled trials evaluating AIs in advanced NSCLC, with survival data on patients who previously received bevacizumab. The end points were overall survival and progression-free survival. Statistical analyses were conducted by using either random effects or fixed effect models according to the heterogeneity of included studies.ResultsA total of 452 patients with advanced NSCLC who previously received bevacizumab were identified for analysis. The meta-analysis results demonstrated that AI rechallenge significantly improved progression-free survival (hazard ratio: 0.72, 95% confidence interval: 0.58–0.89, P=0.002) when compared to non-AI containing regimens. Additionally, a nonsignificant improvement in overall survival was also observed in advanced NSCLC in this setting (hazard ratio: 0.82, 95% confidence interval: 0.65–1.03, P=0.087). Similar results were also observed in subgroup analysis according to treatment regimens.ConclusionThe findings of this study suggest that NSCLC patients who relapsed after a first-line bevacizumab-containing chemotherapy obtain improved clinical benefits from AI rechallenge. Prospective clinical trials investigating the role of AI rechallenge in this setting are recommended.

Window of opportunity: A new insight into sequential bevacizumab and paclitaxel in two cases of metastatic triple-negative breast cancer.

Bevacizumab, an antiangiogenic monoclonal antibody against vascular endothelial growth factor, was designed to normalize tumor vasculature and reduce intratumoral pressure. It can create a 'normalization window' during which the cancer can be attacked the most effectively, and the effects of chemotherapeutic drugs are enhanced. Representative trials (E2100, AVADO, RIBBON-1, RIBBON-2 and TURANDOT) have shown that the addition of bevacizumab to chemotherapy has significant benefits on progression-free survival for metastatic breast cancer, but not on overall survival. The present study describes two patients with metastatic triple-negative breast cancer who received 6 courses of bevacizumab-containing chemotherapy. Each course comprised 5-7.5 mg/kg bevacizumab administered on days 1 and 15, and 20-24 h after bevacizumab delivery, 80 mg/m2 paclitaxel was administered for 3 weeks on days 2, 9 and 16, followed by 1 week of rest. Following sequential treatment with bevacizumab and paclitaxel, the results of computed tomography showed that the tumors were rapidly reduced in size. Based on the imaging findings from three-dimension power Doppler ultrasonography in one of the breast cancer patients who received neoadjuvant chemotherapy with bevacizumab, the possible timing of the normalization window was 20-24 h after the administration of bevacizumab. The normalization window may provide an opportunity to enhance the effect of chemotherapy with the aid of bevacizumab.

Abstract P3-06-09: Plasma biomarker analysis in patients with HER2-negative locally recurrent or metastatic breast cancer (LR/MBC) treated with first-line bevacizumab (A) and paclitaxel (T) without or with capecitabine (X)

Abstract Background The phase II ATX trial aimed at evaluating safety and efficacy of first-line AT or ATX for HER2-negative LR/MBC (NTR1348; BOOG 2006-06). Plasma samples were collected for investigation of circulating proteins involved in angiogenesis and their possible association with therapy outcome. We here report the prognostic value of plasma VEGF-A, soluble (s)VEGFR-2, ANG2, sTIE2, IL6, IL8 and CA9 at baseline (C1D1) and their changes after cycle 1 (C2D1). Methods 312 patients were randomized 1:1 to AT (T 90 mg/m2 d1, 8, 15 &amp; A 10 mg/kg d1, 15 q4w x 6 cycles → A 15 mg/kg d1 q3w for next cycles) or ATX (T 90 mg/m2 d1, 8, A 15 mg/kg d1 &amp; X 825 mg/m2 bid d1–14 q3w x 8 cycles → A &amp; X at same dose q3w for next cycles). Plasma proteins were measured by immunoassays (R&amp;D Systems and MSD). The association of (continuous) protein levels on C1D1 and their changes on C2D1 with response, PFS and OS were evaluated by Mann-Whitney U test and univariate Cox regression analysis. Results The biomarker cohort (n=181) and trial cohort had similar baseline characteristics and clinical outcome. After a median follow-up of 46 months, there were 178 (98%) PFS events and 152 (84%) deaths. On C1D1, levels of ANG2 and sTIE2 were significantly higher in patients with hormone-receptor positive disease compared to those with triple-negative disease (p=.025 and p=.001, respectively). A high level of VEGF-A was noted in patients with visceral metastases (p=.028) and those with an increasing number of metastatic sites (p=.017). High levels of ANG2, IL6, IL8 and CA9 were significantly associated with poor PFS and OS (Table 1). Protein levels were not associated with response. Table 1. Association of circulating proteins at baseline with PFS and OSPFS HR (95%CI)PFS p-valueOS HR (95%CI)OS p-valueANG22.3 (1.0-4.9).043.1 (1.4-7.0).007IL61.6 (1.1-2.3).021.9 (1.3-2.8).001IL81.9 (1.3-2.8).0012.8 (1.8-4.3)&amp;lt;.001CA91.8 (1.2-2.7).0061.9 (1.3-2.9).002 On C2D1, levels of all proteins, except for IL6, had significantly changed. Whereas VEGF-A, ANG2, sTIE2 and IL8 decreased significantly, sVEGFR2 and CA9 showed a significant increase. The median relative change of both IL8 and sVEGFR2 was significantly different between patients having CR/PR vs. SD/PD (for IL8: -19.4% vs. 22.3%, p=.001 and for sVEGFR2: 6.5 vs. 2.1%, p=.01). A large relative increase in CA9 level was associated with better PFS (HR = 0.36, 95% CI, 0.19 – 0.68, p=.002) and OS (HR = 0.50, 95% CI, 0.27 – 0.94, p=.03). All patients had very low levels of free VEGF-A on C2D1 (median 8 pg/ml). Conclusions In patients with HER2-negative LR/MBC receiving first-line bevacizumab-containing chemotherapy, high baseline plasma levels of ANG2, IL6, IL8 and CA9 indicate a high risk for poor PFS and OS. These proteins might be useful for stratification according to prognosis. Moreover, relative decrease in IL8 and increase in sVEGFR2 on C2D1 are associated with response, whereas a large relative increase in CA9 is associated with better PFS and OS. Changes in these proteins after one cycle might be early indicators of efficacy of bevacizumab combined with chemotherapy. Financial support from Roche Netherlands. Citation Format: Siu W Lam, Nienke M Nota, Steffen M de Groot, Agnes Jager, Monique MEM Bos, Sabine C Linn, Joan van den Bosch, Hans J Braun, Ankie MT van der Velden, Maartje Los, Johanneke EA Portielje, Judith R Kroep, Aafke H Honkoop, Carolien H Smorenburg, Bea Tanis, Johanna MGH van Riel, Jetske M Meerum Terwogt, Marien O den Boer, Joep Douma, Frank Jeurissen, Johan Berends, Harm van Tinteren, Epie Boven. Plasma biomarker analysis in patients with HER2-negative locally recurrent or metastatic breast cancer (LR/MBC) treated with first-line bevacizumab (A) and paclitaxel (T) without or with capecitabine (X) [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-06-09.

Initial Experience of Monitoring Response of Breast Cancer to Bevacizumab-containing Chemotherapy using A New Integrin Specific PET Imaging Tracer [F-18]RGD-K5

This study investigates the use of [F-18]RGD-K5, an integrin αvβ3 targeting PET tracer, in breast cancer patients receiving chemotherapy with bevacizumab (Avastin®). Two patients were analyzed: Subject-1 had metastatic breast cancers and Subject-2 had a primary cancer in the breast. The therapy regimen was weekly paclitaxel and carboplatin combined with bi-weekly bevacizumab. Each subject received 5 PET-CT scans: pre-treatment [F-18]RGD-K5 and [F-18]FDG, one [F-18]RGD-K5 F/U scan after 2 doses of bevacizumab, and another [F-18]RGD-K5 and [F-18] FDG F/U after 4 doses of bevacizumab. Many lesions in Subject-1 showed a high [F-18]RGD-K5 baseline uptake. The two most [F-18]RGD-K5 avid lesions had SUVs of 10.8 and 10.1, and the corresponding [F-18]FDG uptakes were much lower (SUV of 1.0 and 3.5). The [F-18]RGD-K5 SUVs in all analyzed lesions decreased during treatment, showing a mean of 34% reduction after 2 doses, and 47% reduction after 4 doses of bevacizumab. The changes in the [F-18]FDG SUVs were much smaller, with a mean reduction of 24%. In contrast to the patient with metastatic cancer, the primary tumor in Subject-2 showed a low [F-18]RGD-K5 uptake (SUV=1.8), but a high [F-18]FDG uptake (SUV=8.7). The [F-18]FDG SUV decreased to 2.4 (72% reduction) after 4 doses of bevacizumab, while the [F-18] RGD-K5 uptake remained unchanged. The results that [F-18]RGD-K5 avid lesions show a great SUV reduction after bevacizumab treatment suggest that the [F-18]RGD-K5 tracer may be potentially used for selecting candidate patient for receiving bevacizumab, as well as in monitoring of the early treatment changes.

IS7-3 - Current Status and Future Perspective of Therapeutic Strategy for Metastatic Colorectal Cancer in Japan

In the last decade, unprecedented advances have been seen in the treatment of metastatic colorectal cancer (mCRC). Clinical developments of new active agents such as irinotecan, oxaliplatin, bevacizumab, cetuximab and panitumumab have contributed to this great progress in the prognosis of mCRC. Recently, a multikinase inhibitor called regorafenib showed survival benefits for patients with mCRC who are refractory to all standard therapies. Also, a novel oral nucleoside antitumor agent known as TAS-102 showed promising efficacy in the same population. Therefore, there is current positive development of various new drugs. On the other hand, the development of many active agents and combination chemotherapies has caused the treatment strategy for mCRC to be complicated. So it is necessary to settle clinical questions in order to optimize this complex treatment strategy. With regard to first line chemotherapy, two major clinical questions remain. The first question is whether bevacizumab or anti-EGFR antibodies are more effective for patients with previously untreated KRAS wild-type mCRC. Last year, the PEAK and FIRE-3 studies showed promising survival benefits for anti-EGFR antibody-containing chemotherapy compared with bevacizumab-containing chemotherapy, and the result of the CALGB80405 trial will be presented at the ASCO annual meeting this year. The second question is whether oxaliplatin or irinotecan-based chemotherapy is more suitable for molecular targeting agents. The West Japan Oncology Group conducted a randomized, open-label, phase III trial (4407G study) to assess the non-inferiority of FOLFIRI + bevacizumab to mFOLFOX6 + bevacizumab in progression-free survival. In this session, I would like to introduce the result of the WJOG4407G study and discuss the future perspective of treatment strategy for mCRC.

P2-18-2 - Safety and Efficacy of Bevacizumab-Containing Chemotherapy in Nsclc Patients with Brain Metastases

Background: Prior to 2012, bevacizumab was contraindicated for patients with brain metastases in Japan due to concerns about cerebral hemorrhage. The package insert changed in 2012 to allow careful administration of bevacizumab; however, we still have insufficient data describing the safety and efficacy of bevacizumab-containing chemotherapy. Because bevacizumab may be effective in the treatment of edema associated with brain metastases and radiation necrosis, it may have additional clinical uses.Methods: We retrospectively evaluated non-small cell lung cancer (NSCLC) patients with brain metastases who had received chemotherapy containing bevacizumab at Chiba Cancer Center between April 2012 and December 2013.Results: Thirty patients were eligible for participation in this study. Of the patients in this study, 15 were men, and 15 were women; patients had a median age of 62.5 years, and all except one had histological adenocarcinoma. Surgery, stereotactic radiosurgery, whole brain radiation, and other therapies were performed in 9, 13, 2, and 1 patients, respectively; 5 patients were not treated. Additionally, 26, 1, 2, and 1 patients received the following chemotherapies: CBDCA + PTX + BEV, CDDP + PEM + BEV, PEM + BEV, or BEV monotherapy, respectively. RECIST classifications of brain metastases were complete response in 2 patients, partial response in 7 patients, stable disease in 11 patients, progressive disease in 1 patients, and NE in 9 patients. Grade 3 adverse events included sensory neuropathy in 1 patient, epileptic seizure in 1 patient, dysbasia in 1 patient, viral encephalitis in 1 patient, febril neutropenia in 1 patient, and subcutaneous abscess of the buttocks in 1 patient. Grade 4 epileptic seizure was occurred in 1 patient. There were no cerebral hemorrhage.Conclusion: Bevacizumab did not increase toxicities in patients with brain metastases and appeared to be effective in the treatment of NSCLC patients with brain metastases.

Targeting metastatic colorectal cancer - present and emerging treatment options.

Metastatic colorectal cancer is a significant cause of morbidity and mortality in the US and around the world. While several novel cytotoxic and biologic therapies have been developed and proven efficacious in the past two decades, their optimal use in terms of patient selection, drug combinations, and regimen sequences has yet to be defined. Recent investigations regarding anti-epidermal growth factor receptor therapies include the comparison of single-agent panitumumab and cetuximab, the benefit of adding cetuximab to chemotherapy in the conversion therapy setting, the comparison of cetuximab and bevacizumab when added to first-line chemotherapy, and predictive biomarkers beyond KRAS exon 2 (codons 12 and 13) mutations. With respect to anti-vascular endothelial growth factor therapies, new data on continuing bevacizumab beyond disease progression on a bevacizumab-containing chemotherapy regimen, the addition of bevacizumab to triplet chemotherapy in the first-line setting, maintenance therapy with bevacizumab plus either capecitabine or erlotinib, the addition of aflibercept to chemotherapy, and regorafenib as monotherapy have emerged. Recent scientific and technologic advances in the field of metastatic colorectal cancer promise to elucidate the biological underpinnings of this disease and its therapies for the goal of improving personalized treatments for patients with metastatic colorectal cancer.