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Rapid growth of primary uveal melanoma following intravitreal bevacizumab injection: a case report and review of the literature.
Ma, J, Roelofs, KA, Russell, L, Weis, E, Chen, SH
Digital journal of ophthalmology : DJO. 2021;(3):27-30
Abstract
Uveal melanoma size is a significant predictor of tumor metastasis. Although the relationship between antivascular endothelial growth factors (VEGF) and uveal melanoma growth has been studied, results are paradoxical, and the relationship remains controversial. We report the case of a 65-year-old man who presented with elevated intraocular pressure in his right eye, neovascularization of his iris, and significant corneal edema, which obscured the view of the angle. Given his history of proliferative diabetic retinopathy, he was diagnosed with neovascular glaucoma and subsequently received an intravitreal injection of bevacizumab and underwent Ahmed valve insertion. This was complicated by postoperative hyphema. Two and a half months postoperatively, a mass involving the inferior iris and ciliary body became visible, and fine-needle aspiration biopsy confirmed uveal melanoma. Seven weeks after diagnosis, the tumor's largest basal diameter had increased from 2.51 mm to 18.0 mm, and apical height increased from 6.23 mm to 11.0 mm. His right eye was enucleated. Histopathological analysis showed discontinuous invasion next to the Ahmed valve. Tumor progression after injection raises the possibility that in some untreated uveal melanomas, accelerated growth may occur following exposure to anti-VEGF agents.
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Bevacizumab as maintenance therapy in patients with metastatic colorectal cancer: A meta-analysis of individual patients' data from 3 phase III studies.
Salvatore, L, Bria, E, Sperduti, I, Hinke, A, Hegewisch-Becker, S, Aparicio, T, Le Malicot, K, Boige, V, Koeberle, D, Baertschi, D, et al
Cancer treatment reviews. 2021;:102202
Abstract
BACKGROUND The real impact of bevacizumab maintenance as single agent in metastatic colorectal cancer (mCRC) remains unclear. SAKK-41/06 and PRODIGE-9 failed to demonstrate the non-inferiority and superiority of bevacizumab versus no maintenance, respectively, while AIO-KRK-0207 showed the non-inferiority of maintenance bevacizumab versus bevacizumab and fluoropyrimidines for time to strategy failure. METHODS Bibliography electronic databases (PubMed, MEDLINE, Embase, Scopus, Web of Science, and the Cochrane Central Register of Controlled Trials) were searched for English published clinical trials prospectively randomizing mCRC patients to receive bevacizumab maintenance or not after first-line chemotherapy plus bevacizumab. Individual patients' data (IPD) were provided by investigators for all included trials. Primary end-points were progression-free survival (PFS) and overall survival (OS), both from the start of induction and maintenance. Univariate and multivariate analyses for PFS and OS were performed. RESULTS Three phase III studies - PRODIGE-9, AIO-KRK-0207 and SAKK-41/06 - were included. Considering the different timing of randomization, IPD of patients not progressed during induction and starting maintenance phase entered the analysis. 909 patients were included, 457 (50%) received bevacizumab maintenance. Median PFS from induction start was 9.6 and 8.9 months in bevacizumab group versus no maintenance group, respectively (HR 0.78; 95%CI: 0.68-0.89; p < 0.0001). Subgroups analysis for PFS showed a significant interaction according for RAS status (p = 0.048), with a maintenance benefit limited to RAS wild-type patients. No difference in terms of OS was observed. CONCLUSIONS Despite the statistically significant PFS improvement for bevacizumab maintenance, the absolute benefit appears limited. Subgroup analysis shows a differential effect of bevacizumab maintenance in favor of RAS wild-type patients. Considering these results, maintenance therapy with fluoropyrimidine with or without bevacizumab remains the first option. Single agent bevacizumab maintenance can be considered in selected cases, such as cumulative toxicity or patient's refusal, in particular for RAS wild-type patients.
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The efficacy and safety of bevacizumab combined with FOLFOX regimen in the treatment of advanced colorectal cancer: A systematic review and meta-analysis.
Zhang, H, You, J, Liu, W, Chen, D, Zhang, S, Wang, X
Medicine. 2021;(30):e26714
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Abstract
BACKGROUND It is necessary to systematically evaluate the clinical efficacy and safety of bevacizumab (BEV) combined with 5-fluorouracil + leucovorin + oxaliplatin (FOLFOX) regimen in the treatment of advanced colorectal cancer. METHODS We searched the PubMed et al databases for randomized controlled trials (RCTs) on the BEV combined with the FOLFOX regimen in the treatment of advanced colorectal cancer up to January 20, 2021. The Cochrane Collaborations' risk of bias tool was used for the quality assessment of included RCTs. Revman5.3 software was used for meta-analysis. RESULTS Eleven RCTs with a total of 3178 patients with advanced colorectal cancer were included, meta-analysis results showed that the objective response rate (odds ratio [OR] = 3.15, 95% confidence intervals [CI]: 2.25-4.40, P < .001) and cancer control rate (OR = 2.73, 95% CI: 1.91-3.90, P < .001) of BEV + FOLFOX were higher than that of FOLFOX group. And the incidence of gastrointestinal adverse reactions (OR = 1.29, 95% CI: 1.07-1.55, P = .008) in the BEV + FOLFOX group was higher than that of the FOLFOX group, there were no significant differences in the incidence of leukopenia (OR = 1.04, 95% CI: 0.72-1.50, P = .83), hypertension (OR = 3.92, 95% CI: 0.81-18.88, P = .09) and neurotoxicity (OR = 1.00, 95% CI: 0.8-1.27, P = .98) between the 2 groups. CONCLUSION BEV combined with the FOLFOX regimen is more effective than the FOLFOX regimen alone in the treatment of advanced colorectal cancer, but it may also increase the risk of gastrointestinal adverse reactions.
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FOLFIRI plus cetuximab or bevacizumab for advanced colorectal cancer: final survival and per-protocol analysis of FIRE-3, a randomised clinical trial.
Heinemann, V, von Weikersthal, LF, Decker, T, Kiani, A, Kaiser, F, Al-Batran, SE, Heintges, T, Lerchenmüller, C, Kahl, C, Seipelt, G, et al
British journal of cancer. 2021;(3):587-594
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BACKGROUND Cetuximab plus FOLFIRI improved overall survival compared with bevacizumab plus FOLFIRI in KRAS wild-type metastatic colorectal cancer (mCRC) in FIRE-3, but no corresponding benefit was found for progression-free survival. This analysis aimed to determine whether cetuximab improves response and survival versus bevacizumab among response-evaluable patients receiving first-line FOLFIRI for RAS wild-type mCRC and the effect of primary tumour side on outcomes. METHODS The intent-to-treat population included 593 patients with KRAS exon 2 wild-type mCRC. Further testing identified 400 patients with extended RAS wild-type disease; of these, 352 (88%) who received ≥3 cycles of therapy and had ≥1 post-baseline scan were evaluable for response and constituted the per-protocol population (169 cetuximab and 183 bevacizumab). Patients received 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) with either weekly cetuximab or biweekly bevacizumab given on day 1 of each 14-day cycle until response, progression or toxicity occurred. The primary endpoint was the objective response rate (ORR) in the per-protocol population. Secondary endpoints included overall survival (OS) and progression-free survival (PFS). The effect of primary tumour location was evaluated. RESULTS Median OS in the RAS wild-type population was 31 vs 26 months in the cetuximab and bevacizumab groups, respectively (HR 0.76, P = 0.012). In the per-protocol population, outcomes favoured cetuximab for ORR (77% vs 65%, P = 0.014) and median OS (33 vs 26 months, HR 0.75, P = 0.011), while PFS was comparable between groups. The advantage of cetuximab over bevacizumab occurred only in patients with left-sided primary tumours. CONCLUSIONS FOLFIRI plus cetuximab resulted in a significantly higher ORR and longer OS compared to FOLFIRI plus bevacizumab among patients with left-sided tumours. The superior response associated with cetuximab may particularly benefit patients with symptomatic tumours or borderline-resectable metastases. CLINICALTRIALS. GOV IDENTIFIER NCT00433927.
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Effectiveness of Combining Bevacizumab With First-Line Chemotherapy Regimens for Metastatic Colorectal Cancer in Real-World Practice.
Bang, YH, Hong, YS, Lee, JS, Lee, KW, Han, HS, Kim, SY, Kim, JW, Kim, HK, Kim, JW, Eun, CK, et al
Clinical colorectal cancer. 2021;(2):101-112.e6
Abstract
BACKGROUND Anti-vascular endothelial growth factor (VEGF) agents have shown clinical benefits against metastatic colorectal cancer (mCRC) when combined with cytotoxic chemotherapeutic drugs. Because randomized controlled trials have restrictive enrollment criteria, and because the participants typically do not resemble actual patients, we here investigated the efficacy of bevacizumab as part of a combination therapy for mCRC in a Korean real-world practice setting. PATIENTS AND METHODS We retrospectively evaluated 3748 patients with an initial diagnosis of mCRC or recurrent colorectal cancer with distant metastasis who received first-line chemotherapy in a tertiary cancer center. The primary study endpoint was overall survival. We used multivariate analysis using the Cox regression hazard model and propensity score matching (PSM) methods to adjust for any confounding clinicopathologic factors. Subgroup analysis was also performed for patients who did not receive local treatments for metastatic lesions before receipt of first-line chemotherapy. RESULTS In an initial crude analysis, patients who received first-line FOLFOX or FOLFIRI showed better survival outcomes if these regimens were combined with bevacizumab (median overall survival, 3.5 vs. 2.3 years; hazard ratio [HR] = 0.66; 95% confidence interval [CI], 0.59-0.73; P < .001). However, Cox regression hazard model adjusted analysis using PSM methods revealed no significant survival differences between these groups (3.0 vs. 2.6 years; HR = 0.92; 95% CI, 0.79-1.07; P = .2612). We performed further survival analysis of 2814 patients with unresectable disease without metastasectomy who received metastatic radiofrequency ablation before chemotherapy. Cox regression and PSM analysis indicated that bevacizumab group showed better survival (HR = 0.82; 95% CI, 0.71-0.94; P = .005; and HR = 0.84; 95% CI, 0.71-0.99; P = .018). CONCLUSION The addition of bevacizumab to a first-line chemotherapeutic regimen provides survival benefits in a real-world setting for mCRC patients who cannot undergo curative-intent local treatment for metastatic lesions.
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Aqueous humor monocyte chemoattractant protein-1 predicted long-term visual outcome of proliferative diabetic retinopathy undergone intravitreal injection of bevacizumab and vitrectomy.
Lei, J, Ding, G, Xie, A, Hu, Y, Gao, N, Fan, X
PloS one. 2021;(3):e0248235
Abstract
PURPOSE We aim to investigate the risk factors associated with the prognosis of proliferative diabetic retinopathy (PDR) after a sequential treatment of intravitreal injection of bevacizumab (IVB) and pars plana vitrectomy (PPV). METHODS In this cohort study, 63 eyes from 55 patients (21 females) diagnosed with PDR, who needed PPV for non-clearing vitreous hemorrhage or fibrovascular membrane proliferation were enrolled. All the eyes underwent IVB followed by PPV. Anterior chamber tap was performed at the beginning of both procedures to evaluate the concentration of vascular endothelial growth factor (VEGF), interleukin (IL)-6, IL-8, and monocyte chemoattractant protein (MCP)-1. RESULTS Forty-seven patients (54 eyes) were followed over six months, averaging 12±5 (6-19) months. The concentration of VEGF significantly decreased after IVB (P<0.001), while other cytokines did not change significantly. The aqueous humor level of IL-8 after IVB (R = 0.378, P = 0.033), MCP-1 before (R = 0.368, P = 0.021) and after (R = 0.368, P = 0.038) IVB, and combined phacoemulsification (R = 0.293, P = 0.032) was correlated with the logMAR visual acuity at the last follow-up. Multivariate analysis showed that MCP-1 was the predictor for a worse visual outcome (B = 0.108, 95% CI 0.013-0.202; P = 0.027). CONCLUSIONS MCP-1 was a predictor for the unfavorable visual outcome of PDR after IVB pretreatment and PPV.
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Neurodevelopmental Outcomes after Bevacizumab Treatment for Retinopathy of Prematurity: A Meta-analysis.
Tsai, CY, Yeh, PT, Tsao, PN, Chung, YE, Chang, YS, Lai, TT
Ophthalmology. 2021;(6):877-888
Abstract
PURPOSE To evaluate neurodevelopmental outcomes after intravitreal bevacizumab (IVB) therapy in retinopathy of prematurity (ROP) infants compared with those not exposed to IVB. CLINICAL RELEVANCE The primary concern regarding IVB treatment of ROP is the potential systemic side effects, especially the risk of causing severe neurodevelopmental impairment (sNDI). Results regarding neurodevelopmental outcomes after IVB therapy are conflicting. METHODS We conducted a meta-analysis and searched PubMed, Embase, and Web of Science for related publications from inception through March 12, 2020. The eligibility criteria were as follows: comparative studies of ROP patients that (1) included IVB as a treatment arm, (2) included a control group without bevacizumab treatment, and (3) reported on at least 1 neurodevelopmental outcome, such as sNDI, Bayley Scales of Infant and Toddler Development, Third Edition (Bayley III), composition scores, or cerebral palsy (CP). The primary outcome was sNDI, with the odds ratio (OR) calculated. Secondary outcomes were mean differences (MDs) for cognitive, language, and motor scores (Bayley III) and OR for CP. The quality of evidence was assessed using the Grades of Recommendation, Assessment, Development, and Evaluation approach. RESULTS Eight studies, 6 including laser-controlled ROP infants and 2 including ROP infants not requiring treatment, were included. The weighted OR for sNDI in the IVB group was 1.39 (95% confidence interval [CI], 0.98-1.97). The weighted MDs were -1.92 (95% CI, -4.73 to 0.88), -1.32 (95% CI, -4.65 to 1.99), and -3.66 (95% CI, -6.79 to -0.54) for cognitive, language, and motor scores in Bayley III, respectively. The OR for CP was 1.20 (95% CI, 0.56-2.55). No differences were observed between the preset subgroups comprising laser-controlled ROP infants and ROP infants not requiring treatment. The current quality of evidence was rated as low (sNDI and all Bayley III scores) to very low (CP). CONCLUSIONS Risk of sNDI was not increased in ROP patients after IVB treatment. Bayley III scores were similar in the IVB and control groups, except for a minor difference in motor performance. These findings suggest that the risk of additional sNDI after IVB treatment is low. Randomized trials are warranted to provide a higher quality of evidence.
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Predictors of Visual Acuity Outcomes after Anti-Vascular Endothelial Growth Factor Treatment for Macular Edema Secondary to Central Retinal Vein Occlusion.
Sen, P, Gurudas, S, Ramu, J, Patrao, N, Chandra, S, Rasheed, R, Nicholson, L, Peto, T, Sivaprasad, S, Hykin, P
Ophthalmology. Retina. 2021;(11):1115-1124
Abstract
PURPOSE To evaluate whether baseline demographic, clinical, and OCT characteristics predict visual acuity (VA) outcomes in patients receiving anti-vascular endothelial growth factor (VEGF) therapy for macular edema (ME) due to central retinal vein occlusion (CRVO). DESIGN Post hoc analysis of the randomized noninferiority trial (Lucentis, Eylea, Avastin in CRVO) LEAVO Study from December 12, 2014, to December 16, 2016, carried out across 44 UK National Health Service ophthalmology departments. PARTICIPANTS Data on 267 participants with a baseline best-corrected mean visual acuity (BCVA) range of 19 to 78 Early Treatment Diabetic Retinopathy Study letter score (approximate Snellen equivalent, 20/32 to 20/320) who had central subfield thickness (CST) ≥ 320 μm on Spectralis OCT (Heidelberg Engineering) were analyzed. METHODS Study participants were randomized to receive repeated intravitreal injections of ranibizumab (0.5 mg/50 μl), aflibercept (2.0 mg/50 μl), or bevacizumab (1.25 mg/50 μl), and a protocol-driven pro re nata re-treatment regimen at 4 to 8 weekly visits was followed up to week 100 after 4 mandated 4-weekly loading injections. MAIN OUTCOME MEASURES Change in BCVA and percentage of patients gaining ≥ 10 letters and achieving BCVA letter score > 70 letters at 52 and 100 weeks. RESULTS The analysis was adjusted for treatment effects and confirmed by sensitivity analysis. Age ≥ 75 years is a poor predictor for all 3 visual outcomes. Lower baseline BCVA predicted 10-letter gainers and higher gains in BCVA, although it is a poor predictor of achieving > 70 Early Treatment Diabetic Retinopathy Study letters. None of the baseline OCT morphologic characteristics except ellipsoid zone (EZ) integrity influenced any visual outcomes. Both baseline CST and total macular volume showed a nonlinear relation to 10-letter gainers, with CST > 900 μm being a poor prognostic indicator. Baseline CST and macular volume did not predict mean change in BCVA or BCVA > 70 letters at 52 and 100 weeks. The sensitivity analysis conclusions after removing iCRVO were similar. CONCLUSIONS At presentation, younger age, higher baseline BCVA, and a definitely intact subfoveal EZ are predictors of BCVA score > 70 letters at 100 weeks.
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Intravoxel Incoherent Motion of Colon Cancer Liver Metastases for the Assessment of Response to Antiangiogenic Treatment: Results from a Pilot Study.
Öz, A, Server, S, Koyuncu Sökmen, B, Namal, E, İnan, N, Balcı, NC
Medical principles and practice : international journal of the Kuwait University, Health Science Centre. 2020;(5):429-435
Abstract
OBJECTIVE This study was aimed at evaluating the intravoxel incoherent motion (IVIM) parameter alterations of liver metastases of colorectal carcinoma (CRC) during antiangiogenic bevacizumab combination therapy. METHODS Twenty-five patients with CRC liver metastases treated with bevacizumab in combination with FOLFOX-or-FOLFIRI protocols were enrolled in the study. MRI was performed using a 1.5-tesla scanner pre-treatment (PT) and at 3, 6, and 9 months of therapy. Routine abdominal MRI sequences and an IVIM-DWI (diffusion-weighted imaging) sequence were obtained. The IVIM-DWI sequence was executed with 16 b-values varying from 0 to 1,400 s/mm2. The mean values of apparent diffusion coefficient (ADC), true diffusion (D), pseudodiffusion (D*), and perfusion fraction (f) of each metastasis were obtained for all b-values, and the time-related changes were recorded to analyze the chronologic responses to antiangiogenic therapy. The RECIST 1.1 criteria were used for the evaluation of treatment response. RESULTS The diameters of the metastases diminished significantly at 9 months when compared with PT (p = 0.03). The D (p = 0.10) and ADC (p = 0.21) values of the metastases increased at 9 months of therapy. D* was the highest at 3 months (p =0.24); it decreased at 6 (p =0.97) and 9 months (p =0.87) of therapy. The f value had peaked at 3 months (p =0.51) and started to decrease thereafter. At 6 months, f decreased to the lowest values (p =0.12). CONCLUSION IVIM parameters, particularly the perfusion fraction, may quantitatively reflect the response to antiangiogenic treatment. The antiangiogenic response manifests after 3 months of therapy before the RECIST-related response.
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Efficacy and Safety of Proposed Bevacizumab Biosimilar BE1040V in Patients With Metastatic Colorectal Cancer: A Phase III, Randomized, Double-blind, Noninferiority Clinical Trial.
Rezvani, H, Mortazavizadeh, SM, Allahyari, A, Nekuee, A, Najafi, SN, Vahidfar, M, Ghadyani, M, Khosravi, A, Qarib, S, Sadeghi, A, et al
Clinical therapeutics. 2020;(5):848-859
Abstract
PURPOSE The purpose of this study was to compare the efficacy and safety of a proposed bevacizumab biosimilar to those of the reference product in patients with metastatic colorectal cancer (mCRC). METHODS This Phase III, multicenter, randomized, double-blind (patient- and assessor-blind), active-controlled, 2-armed, parallel-group, noninferiority trial was conducted in patients with histologically verified colorectal cancer with evidence of at least 1 metastasis. Patients with mCRC were randomized 2:1 to receive 5 mg/kg IV of either study drug plus FOLFIRI-3 (with repeated irinotecan 100 mg/m2 60-min infusion on day 3) or the reference drug plus FOLFIRI-3 every 2 weeks for 1 year. Progression-free survival (PFS) was the primary end point, and overall survival, objective response rate, and time to treatment failure as well as safety and immunogenicity were secondary end points. The population assessable for PFS was per protocol, and the intention-to-treat population was used for sensitivity analysis. Safety was assessed based on reports of adverse events, laboratory test results, and vital sign measurements. FINDINGS A total of 126 patients were enrolled; PFS values in the biosimilar and reference arms were 232 days (7.7 months) and 210 days (7 months), respectively (P = 0.47). The hazard ratio of the biosimilar arm versus the reference arm was 0.79 in the per-protocol population (90% CI, 0.46-1.35; P = 0.47). The upper limit for the 2-sided 90% CI was lower than the margin of 1.44, indicating that the biosimilar drug was noninferior to the reference drug. The hazard ratio for overall survival in the intent-to-treat population was 0.99 (95% CI, 0.55-1.80; P = 0.99). The difference between other efficacy end points among the groups was not statistically significant. No significant difference was observed in the comparison of the two arms for safety. The antidrug antibody was positive in 1 patient in each arm. IMPLICATIONS The proposed biosimilar BE1040V was noninferior to the reference product in terms of efficacy in the treatment of mCRC, and tolerability was comparable between the 2 drugs. ClinicalTrials.gov identifier: NCT03288987.