Bevacizumab-containing Chemotherapy Research Articles

TIE2-expressing myeloid cells as a predictive marker for bevacizumab-containing chemotherapy in metastatic colorectal cancer.

e14046 Background: The purpose of this study was to investigate the potential of TIE2-expressing myeloid cells (TEMs) and tumor-associated stroma cells (TASCs) as surrogate markers of clinical outc...

A patient presenting nasal septum perforation during bevacizumab-containing chemotherapy for advanced breast cancer

Nasal septum perforation is a rare but described complication of the anti-angiogenetic agent bevacizumab. This is the case of a 48-year-old female breast cancer patient, who developed a nasal septum perforation during treatment with paclitaxel and bevacizumab for advanced disease. After 2 cycles the patient developed nasal irritation and occasional epistaxis; after the 4th cycle with bevacizumab the symptoms worsened to include nasal congestion, major epistaxis and rhinorrhoea. Anterior rhinoscopy revealed a large perforation involving the antero-inferior portion of the cartilaginous nasal septum surrounded by necrotic mucosa. The upper septum and the columellar strut were intact. The patient denied use of cocaine or other intranasal irritants. Bevacizumab was discontinued and with only a topical intranasal vitamin application the symptoms improved. One month later anterior rhinoscopy showed that the lesion healed and normal mucosa surrounded the previous site of perforation. The patient continued successfully with other chemotherapy regimens (gemcitabine and then vinorelbine) until irreversible progressive disease led to her death in February 2010. Thus far 8 other cases of bevacizumab-related nasal septum perforation have been published: 5 patients with colorectal cancer, 2 patients with breast cancer and 1 with ovarian cancer. Nasal septum perforation is an emerging challenge with targeted therapies and in particular with antiangiogenetic or antivascular agents. A rapid diagnosis is important and hence we recommend that patients undergoing treatment with bevacizumab and presenting with nasal symptoms (epistaxis, crusting, rhinorrhoea, nasal congestion and local pain or irritation) should undergo anterior rhinoscopy immediately.

Relative impact of chemotherapy with or without bevacizumab on cytokines and angiogenic factors (CAFs) in metastatic colorectal cancer.

401 Background: CAFs were previously shown to be modulated in patients (pts) with metastatic colorectal cancer (mCRC) after bevacizumab-containing chemotherapy. Validation of these prior findings is warranted. In addition, the relative impact of bevacizumab and the cytotoxic chemotherapy components on CAFs has not been previously described. Methods: Plasma samples from 403 mCRC pts were obtained prior to any chemotherapy (Group A) or after progression on a regimen without or with bevacizumab (Group B and C, respectively) between 2002 and 2008. Samples were matched for number of metastatic disease sites (Groups A, B, C) and for prior chemotherapy duration, and time from last chemotherapy dose to sample collection (Groups B, C). Levels of 48 CAFs were measured by suspension bead multiplex assays (BioRad and EMD). Comparisons of Groups A v C (n=169 pairs) and Groups B v C (n=65 pairs) were by the two-sided, nonparametric Wilcoxon paired test, with p<0.05 significance for confirmation of previous CAF results. Results: Prior chemotherapy duration (6.5mo, 6.7mo), and time from last chemotherapy dose to sample collection (1.3mo, 1.2 mo) were similar for Groups B and C, respectively. Results were available for 80% of the samples. Compared to Group A, Group B had reductions in multiple CAFs, including IL-8 (-38%, p<0.0001) and PDGF (-62%, p<0.0001). Commensurate with prior results, PlGF, Eotaxin and TRAIL were increased in Group C by 30% (p<0.0001), 23% (p=0.024) and 19% (p=0.008) respectively. Most CAF changes were attributable to chemotherapy alone. However, PlGF (-31%, p<0.0001) and TRAIL (+26%, p=0.037) significantly differed in Groups B v C. In group C compared to A, multiple changes were seen in the EGFR-axis including decreases in EGF (-52%, p=0.032), epiregulin (-25%, p=0.0023), and HB-EGF (-40%, p<0.0001) as well as an increase in sEGFR (+10%, p=0.004). Conclusions: Most changes in CAFs after treatment with bevacizumab-containing chemotherapy appear to be due to chemotherapy alone and not attributable to anti-VEGF therapy, with several notable exceptions. Chemotherapy-induced changes in the EGFR-axis have not previously been described in mCRC and warrant further investigation. [Table: see text]

Hypertension and overall survival in metastatic colorectal cancer patients treated with bevacizumab-containing chemotherapy

Background:Hypertension (HTN) is a common toxicity of anti-VEGF (vascular endothelial growth factor) antibody treatment. It may be a marker of VEGF signalling pathway inhibition and therefore represent a cancer biomarker in metastatic colorectal cancer (mCRC) patients treated with chemotherapy and bevacizumab.Methods:A total of 101 consecutive patients with mCRC were treated with standard chemotherapy combined with bevacizumab at dose of 2.5 mg kg−1 per week in a single centre. The median follow-up time of the patients alive was 64 months. Blood pressure was measured before each bevacizumab infusion, and HTN was graded according to common toxicity criteria for adverse events version 3.0.Results:Overall, 57 patients (56%) developed ⩾grade 1 HTN (median blood pressure 168/97 mm Hg), whereas 44 (44%) remained normotensive when treated with bevacizumab-containing chemotherapy regimen. Overall response rate was higher among patients with HTN (30 vs 20% P=0.025). Hypertension was associated with improved progression-free survival (10.5 vs 5.3 months; P=0.008) and overall survival (25.8 vs 11.7 months; P<0.001), and development of HTN within 3 months had an independent, prognostic influence in a multivariate landmark survival analysis together with other known mCRC prognostic factors (P=0.007). There was no association between HTN and development of thromboembolic complications.Conclusion:Hypertension may predict outcome of bevacizumab-containing chemotherapy in mCRC. These data require confirmation in prospective studies including pharmacodynamic and pharmacokinetic analyses.

Predictive and prognostic implications of KRAS genotype in patients with metastatic colorectal cancer (MCRC) treated with FIr-B/FOx association.

457 Background: FIr-B/FOx association, consisting of triplet chemotherapy (FIr/FOx) plus bevacizumab, increases activity, efficacy, and resection rate of liver metastases in MCRC patients (Bruera G et al, submitted 2010). Even if bevacizumab-containing chemotherapy is also active in KRAS m MCRC patients, ORR, PFS, and OS seem to be lower compared to KRAS wt patients (Hurwitz et al, Oncologist 2009). Present data evaluates activity and efficacy of FIr-B/FOX according to KRAS genotype. Methods: Treatment schedule: weekly alternating bevacizumab (5 mg/kg days 1,15)/irinotecan (160 mg/m2) or oxaliplatin (80 mg/m2) associated to weekly 5- fluorouracil (12h-timed-flat-infusion, 900 mg/m2/d 1-2, 8-9, 15-16, 22-23); every 4 weeks. KRAS genotype was analyzed by direct sequencing or SNaPshot (Di Fiore et al, BJC'07) for KRAS codon 12 and 13 mutations. Results: Forty-two (84%) out of 50 enrolled patients (pts) in the FIr-B/FOx phase II study were evaluated: ORR 86% (C.I. ± 11), median PFS 13 months (3-46+), median OS 28 months (8-47). Liver metastasectomies (LM) were performed in 11 pts (26%): 42% of the 26 liver-MCRC pts; 58% of the 19 pts with liver-only MCRC pts. Twenty-five pts (59.5%) were KRAS wild-type (wt), 17 pts (40.5%) KRAS mutated (m). Clinical features were balanced. Among the 25 KRAS wt pts: ORR 88% (C.I. ± 14); median PFS 14 months (3-46+); median OS 31 months (8-47). LM were performed in 9 KRAS wt pts (36%): 56% of the 16 liver-MCRC pts; 82% of the 11 liver-only MCRC pts. Among the 17 KRAS m pts: ORR 82% (C.I. ± 19); median PFS 12 months (4-37+); median OS 19 months (8-44). LM were performed in 3 KRAS m pts (18%): 30% of the 10 liver-MCRC pts; 37.5% of the 8 liver-only MCRC pts. Conclusions: Triplet chemotherapy plus bevacizumab (FIr-B/FOx association) shows equivalent high activity (ORR) and efficacy (PFS) in KRAS wt and KRAS m MCRC pts; a trend toward a worse prognosis (OS) is confirmed in KRAS m pts. No significant financial relationships to disclose.

Pneumothorax After Bevacizumab-containing Chemotherapy: A Case Report

Bevacizumab added to 5-fluorouracil-based chemotherapy can improve outcomes in patients with metastatic colorectal cancer. Bevacizumab had several notable adverse effects including bowel perforation but pneumothorax had never been reported in the available English literature. We reported a 45-year-old male with lung metastases from colorectal cancer who had spontaneous pneumothorax after the second cycle of bevacizumab-containing chemotherapy. His pneumothorax resolved after tube thoracostomy with a small caliber catheter. The mechanism of pneumothorax developed after bevacizumab therapy was not clear as bowel perforation but tumor necrosis with ruptured parietal pleura might be the cause. In patients who had chest discomfort after bevacizumab-containing therapy, pneumothorax should never be overlooked as one of the differential diagnoses.

Perirenal hematoma associated with bevacizumab treatment

We now describe the first example of a patient who developed perirenal hematoma during the course of bevacizumab-containing chemotherapy. A 59-years-old woman with metastatic rectal cancer treated with bevacizumab, who developed low back pain after 11 cycles of chemotherapy. CT-scan was consistent with perirenal hematoma and discontinuation of bevacizumab resulted in symptomatic improvement. Nontraumatic perirenal hematoma is a rare condition that can cause shock in severe cases. Given that several types of bleeding complication are known to be associated with bevacizumab treatment, we concluded that bevacizumab likely contributed to the perirenal hematoma in this case. Although the appropriate modification of bevacizumab treatment in the setting of perirenal hematoma is still unclear, physicians should be aware of this potential bevacizumab-associated bleeding complication.

Therapeutic Significance of a D-dimer Cut-off Level of &gt;3 g/ml in Colorectal Cancer Patients Treated with Standard Chemotherapy plus Bevacizumab

The risk of venous thromboembolism has been reported to increase when receiving bevacizumab. Many cancer patients are reported to have elevated D-dimer levels. It is not clear what D-dimer level might indicate an increased risk of venous thromboembolism in the colorectal cancer patients treated with bevacizumab-containing chemotherapy. The D-dimer levels and any event concurrent with an elevated D-dimer level were evaluated in patients receiving bevacizumab. The D-dimer cut-off level was determined using the receiver-operating characteristic analysis. The selection criteria were as follows: histologically proven metastatic and unresectable colorectal adenocarcinoma; no prior chemotherapy containing bevacizumab; D-dimer test performed repetitively on the baseline and during bevacizumab administration; no venous thromboembolism identified at the baseline; and enhanced computed tomographic scan performed every 2 months. Sixty-nine patients were included. The chemotherapy regimens with bevacizumab included the regimen of 5-fluorouracil, leucovorin and oxaliplatin (FOLFOX), the regimen of 5-fluorouracil, leucovorin and irinotecan (FOLFIRI), and leucovorin-modulated 5-fluorouracil. The median baseline D-dimer level was 1.2 µg/ml. The appropriate D-dimer cut-off level was 3 µg/ml with the negative predictive value of 98% and relative risk of 6.9. Twenty-one of 69 patients showed elevated D-dimer levels of >3 µg/ml, with 11 patients for unknown reasons, 6 with tumor progression, 3 with venous thromboembolism and 1 with sepsis. In the remaining 48 patients whose D-dimer levels were ≤3 µg/ml, only one patient developed a venous thromboembolism. A D-dimer cut-off level of 3 µg/ml might be a useful indicator level to exclude venous thromboembolism or show an increased risk for venous thromboembolism in colorectal cancer patients treated with bevacizumab-containing chemotherapy.

Association of Computed Tomography Morphologic Criteria With Pathologic Response and Survival in Patients Treated With Bevacizumab for Colorectal Liver Metastases

The standard criteria used to evaluate tumor response, the Response Evaluation Criteria in Solid Tumors (RECIST), were developed to assess tumor shrinkage after cytotoxic chemotherapy and may be limited in assessing response to biologic agents, which have a cytostatic mechanism of action. To validate novel tumor response criteria based on morphologic changes observed on computed tomography (CT) in patients with colorectal liver metastases treated with bevacizumab-containing chemotherapy regimens. A total of 234 colorectal liver metastases were analyzed from 50 patients who underwent hepatic resection after preoperative chemotherapy that included bevacizumab at a comprehensive US cancer center from 2004 to 2007; date of last follow-up was March 2008. All patients underwent routine contrast-enhanced CT at the start and end of preoperative therapy. Three blinded, independent radiologists evaluated images for morphologic response, based on metastases changing from heterogeneous masses with ill-defined margins into homogeneous hypoattenuating lesions with sharp borders. These criteria were validated with a separate cohort of 82 patients with unresectable colorectal liver metastases treated with bevacizumab-containing chemotherapy. Response determined using morphologic criteria and RECIST was correlated with pathologic response in resected liver specimens and with patient survival. Interobserver agreement for scoring morphologic changes was good among 3 radiologists (kappa, 0.68-0.78; 95% confidence interval [CI], 0.51-0.93). In resected tumor specimens, the median (interquartile range [IQR]) percentages of residual tumor cells for optimal morphologic response was 20% (10%-30%); for incomplete response, 50% (30%-60%); and no response, 70% (60%-70%; P < .001). With RECIST, the median (IQR) percentages of residual tumor cells were for partial response 30% (10%-60%); for stable disease, 50% (20%-70%); and for progressive disease, 70% (65%-70%; P = .04). Among patients who underwent hepatic resection, median overall survival was not yet reached with optimal morphologic response and 25 months (95% CI, 20.2-29.8 months) with incomplete or no morphologic response (P = .03). In the validation cohort, patients with optimal morphologic response had median overall survival of 31 months (95% CI, 26.8-35.2 months) compared with 19 months (95% CI, 14.6-23.4 months) with incomplete or no morphologic response (P = .009). RECIST did not correlate with survival in either the surgical or validation cohort. Among patients with colorectal liver metastases treated with bevacizumab-containing chemotherapy, CT-based morphologic criteria had a statistically significant association with pathologic response and overall survival.

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.

Perioperative chemotherapy with bevacizumab (BV) for liver metastases (LM) in colorectal cancer (CRC): McGill University pilot study

e15027 Background: Colorectal liver metastases treated with perioperative chemotherapy were previously shown to increase progression free survival. Given the survival benefit of bevacizumab in metastatic CRC, the aim of this study was to assess the efficacy and safety of bevacizumab based chemotherapy in the perioperative setting. Methods: In this single arm prospective pilot study, patients with resectable LM eligible to receive perioperative BV and chemotherapy were included. Kaplan Meier survival analysis was used to calculate overall survival and progression free survival. Results: A total of 60 patients were recruited, 41 male, with an average age of 55. Forty-three patients had synchronous LM. All but seven patients received pre and post-operative BV-based chemotherapy (34/60 oxaliplatin based, 22/60 CPT-11 based and 4/60 CPT-11 and oxaliplatin based). All patients underwent hepatectomy 6–8 weeks post last dose of BV. Overall response rate was 80% (48/60), 4pt with stable diseaase; 10% had a complete pathological response and 27% had no evidence of disease post hepatectomy with a median follow up of 33 months.8 patients progressed prior to surgery. Overall survival (OS) rates at 12, 24, 36 and 48 months were: 100%, 86%, 74% and 66% respectively and 5 year median survival of 55%. Progression free survival (PFS) was 14 months. Subgroup analysis of the data according to the chemotherapy pts received showed that PFS in the CPT-11 and the oxaliplatin arm were 13 and 15 months respectively. Most of the adverse events recorded were associated with the post-operative period and included wound healing (8pts), infections (2pts) and thromboemblic (6pts) disease. No sudden deaths or bowel perforations were reported. Conclusions: Bevacizumab-containing chemotherapy regimens in the peri-operative setting is effective in patients with colorectal liver metastases. Our 80% response rate and 10% complete pathological response is one of the highest reported and warrants further investigation in phase III trials. [Table: see text]

Phase II Trial of Bevacizumab in Combination with Weekly Docetaxel in Metastatic Breast Cancer Patients

To evaluate the safety and efficacy of bevacizumab and weekly docetaxel as first- or second-line therapy in patients with metastatic breast cancer (MBC). Twenty-seven MBC patients received i.v. bevacizumab at 10 mg/kg on days 1 and 15 in combination with i.v. docetaxel 35 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Primary end points were to assess toxicity, overall response rate, and progression-free survival. A secondary end point was to assess the relationship between plasma endothelial and cell adhesion markers and clinical outcomes. One-hundred fifty-eight treatment cycles were administered with a median of six cycles (range 1-15 cycles) per patient. The most common grade 4 toxicities per patient were as follows: 2 (7%)-pulmonary embolus, 1 (4%)-febrile neutropenia, and 1 (4%)-infection; grade 3 toxicities were 4 (15%)-neutropenia, 4 (15%)-fatigue, 2 (7%)-neuropathy, 2 (7%)-athralgias, 2 (7%)-stomatitis, 1 (7%)-pleural effusion, and 1 (4%)-hypertension. The overall response rate was 52% [95% confidence interval (95% CI), 32-71%], median response duration was 6.0 months (95% CI, 4.6-6.5 months), and the median progression-free survival was 7.5 months (95% CI, 6.2-8.3 months). In hypothesis-generating univariate and limited multivariate analyses, E-selectin was statistically significantly associated with response to the combination. Bevazicumab in combination with weekly docetaxel is active with acceptable toxicities in MBC. Additional studies evaluating E-selectin as a marker of response to bevacizumab-containing chemotherapy are warranted.