Bevacizumab-related Toxicity Research Articles

Bevacizumab-Based Therapies in Malignant Tumors-Real-World Data on Effectiveness, Safety, and Cost.

For this purpose, we conducted an open, observational, retrospective study involving all patients treated for solid malignant tumors in the Bucharest Institute of Oncology with "Prof. Dr. Al. Trestioreanu" with Bevacizumab-based systemic therapy, between 2017 and 2021. The study consisted of 657 treatment episodes in 625 patients (F/B = 1.62/1, with a median age of 57.6 years) which were treated for malignant tumors (majority colorectal, non-small cell lung, ovarian, and breast cancer). First-line treatment was administered in 229 patients, and the rest received Bevacizumab as second or subsequent lines of treatment. The overall response rate to Bevacizumab-based therapies was around 60-65% across all indication except for subsequent treatment lines in colorectal and ovarian cancers, where lower values were recorded (27.1%, and 31.5% respectively). Median PFS for the entire cohort was 8.2 months (95% CI 6.8-9.6), and the median OS was 13.2 months (95% CI 11.5-14.9). Usual bevacizumab-related toxicities were observed, including bleeding, hypertension, wound-healing complications, gastrointestinal perforation, other types of fistulas, septic complications, and thromboembolic events. Although the clinical benefits are undeniable, the addition of Bevacizumab to standard chemotherapy increased the overall treatment cost by 213%. Bevacizumab remains a high-cost therapy, but it can add to clinical benefits (like overall survival, progression-free survival, and response rate) when used in conjunction with standard chemotherapy. Similar results as those presented in various controlled trials are observable even on unselected cohorts of patients in the uncontrolled conditions of "real-world" oncological practice. Off-label usage is encountered in clinical practice, and this aspect should be monitored given the potential adverse effects of the therapy.

Systemic complications of intravitreal bevacizumab: a case report and literature review

Background: Systemic complications of intravitreal bevacizumab (IVB) injections have been previously reported. We aimed to summarize the systemic complications reported in online primary studies. Moreover, we describe a patient experiencing simultaneous renal and cutaneous drug-induced adverse effects, with exacerbation of chronic renal insufficiency and granulomatous skin lesions, after receiving several IVB injections to manage bilateral ischemic branch retinal vein occlusion (BRVO). Case Presentation: A 69-year-old Hispanic diabetic man with chronic renal insufficiency due to polyclonal gammopathy received several IVB injections to treat bilateral ischemic BRVO. One week after the sixth injection, the patient developed acute-on-chronic renal failure and multiple rounded maculopapular, erythematous, and ulcerated skin lesions. Renal and skin biopsy specimens revealed granulomatous drug-induced responses in both organs, and granulomatous diseases of infectious and oncological sources were ruled out. We performed an electronic search of the PubMed/MEDLINE database with no language or time restrictions using the keywords “intravitreal bevacizumab” or “intravitreal Avastin” combined with “systemic side effects,” “systemic complications,” or “systemic adverse,” or “systemic adverse event.” The search yielded 147 articles published over almost two decades. After screening and assessment, we selected and summarized 40 primary studies that mentioned IVB-related systemic complications. Conclusions: IVB-induced systemic complications, such as arteriothrombotic events, venous thrombotic events, and hypertension, are rare but potentially serious. Care should be taken when administering multiple doses of intravitreal IVB to patients with pre-existing kidney dysfunction. Bevacizumab-related toxicity must be considered in cases of sudden deterioration of renal function and / or unexpected granulomatous skin lesions in oncologic or chronically polymedicated patients.

A systematic review of targeted therapy for vestibular schwannoma in patients with NF2-related schwannomatosis.

One of the hallmarks of NF2-related Schwannomatosis (NF2-related SWN) is bilateral vestibular schwannomas (VS) that can cause progressive hearing impairment in patients. This systematic review was performed to investigate the efficacy and toxicity of tested targeted agents. The systematic search was conducted on PubMed and EMBASE Ovid databases from inception to October 2022, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The incidence of outcomes in studies involving bevacizumab and other targeted therapies was extracted. The bevacizumab results were pooled, and 95% confidence intervals (95% CI) were calculated. Sixteen studies (8 prospective and 8 retrospective) testing 6 drugs were selected out of 721 search results. There were 10 studies concerning bevacizumab, with a total of 200 patients. The pooled radiographic response rate (RR) was 38% (95% CI: 31 - 45%) and the pooled hearing response rate (HR) was 45% (95% CI: 36 - 54%). The most frequent bevacizumab-related toxicities were hypertension and menorrhagia. Of other targeted therapies showing activity, lapatinib had a RR of 6% and a HR of 31%. A VEGFR vaccine showed RR in 29% and HR in 40% of patients. Both agents had a manageable safety profile. Bevacizumab, in comparison to other targeted agents, showed the highest efficacy. Lower dosage of bevacizumab shows comparable efficacy and may reduce toxicity. Other targeted agents, administered alone or as combination therapy, have the potential to improve outcomes for VS in patients with NF2-related SWN, but future clinical studies are needed.

Long-Term Safety Data on S-1 Administered After Previous Intolerance to Capecitabine-Containing Systemic Treatment for Metastatic Colorectal Cancer

IntroductionThe oral fluoropyrimidine S-1 has shown comparable efficacy to capecitabine in Asian and some Western studies on metastatic colorectal cancer. S-1 is associated with a lower incidence of hand-foot syndrome (HFS) and cardiac toxicity. We assessed the long-term tolerability of S-1 in patients who discontinued capecitabine for reasons of HFS or cardiac toxicity. Patients and MethodsPatients with metastatic colorectal cancer who switched from capecitabine to S-1, given as monotherapy or in combination with other agents, were identified in a Dutch prospective cohort study (2016-2021). The incidence and severity of HFS, cardiotoxicity and other toxicities were assessed. ResultsForty-seven patients were identified. The median duration of capecitabine treatment was 81 days (range 4-454). In 19 patients (40%) a dose reduction was applied prior to switch to S-1. Reasons for discontinuation of capecitabine were HFS in 36 (77%) patients, coronary artery vasospasms in 10 (21%) patients, and gastrointestinal toxicities in 1 patient (2%). The median number of S-1 cycles was 6 (range 1-36). The median time between last dose of capecitabine and first dose of S-1 was 11 days (range 1-49). After switch to S-1, all patients with prior HFS developed a lower grade or complete resolution of symptoms, and in all other patients symptoms did not recur. Other S-1-related adverse events were limited to grade 1-2. Six patients (13%) discontinued S-1 due to either known fluoropyrimidine-related or bevacizumab-related toxicities. Switch to S-1 did not appear to compromise treatment efficacy. ConclusionS-1 is a valid alternative to capecitabine in case HFS or cardiotoxicity occurs.

Erlotinib and bevacizumab in elderly patients ≥75 years old with non-small cell lung cancer harboring epidermal growth factor receptor mutations

The efficacy and safety of combination therapy with erlotinib and bevacizumab in elderly patients with non-small-cell lung cancer (NSCLC) harboring epidermal growth factor receptor (EGFR) gene mutations are unknown. Elderly patients aged ≥75years old with advanced or recurrent NSCLC and EGFR mutations (exon 19 deletion or L858R mutation in exon 21) received erlotinib (150mg, daily) and bevacizumab (15mg/kg on day 1 of a 21-daycycle) until disease progression or the occurrence of unacceptable toxicities. The primary endpoint was progression-free survival from enrollment. Twenty-five patients were enrolled in this study, and the median age was 80years. Fifteen (60.0%) and 10 patients (40.0%) had exon 21 L858R mutations and exon 19 deletions, respectively. The median progression-free survival from enrollment was 12.6months [95% confidence interval (CI): 8.0-33.7months]. The objective response rate was 88.0% [95% CI: 74.0%-99.0%], and the disease control rate was 100% [95% CI: 88.7%-100%]. Grade 3 or higher adverse events occurred in 12 patients (48.0%), and rash and nausea were the most common. Grade 3 or higher bevacizumab-related toxicities occurred in 4 (16.0%) patients, including proteinuria (n = 2), gastrointestinal perforation (n = 1) and pneumothorax (n = 1). A dose reduction of erlotinib and cessation of bevacizumab was required in 16 (64.0%) and 18 patients (72.0%), respectively. Erlotinib and bevacizumab combination therapy showed a minimal survival benefit with frequent dose reductions and/or treatment discontinuations in elderly patients with EGFR-positive NSCLC.

ToleRability of BevacizUmab in elderly Ovarian cancer patients (TURBO study): a case-control study of a real-life experience.

ObjectiveBevacizumab maintenance following platinum-based chemotherapy is an effective treatment for epithelial ovarian cancer (EOC), both in primary and recurrent disease. Our aim was to identify criteria to select elderly patients who can safely benefit from bevacizumab addition.MethodsThis is a case-control study on patients with primary or recurrent EOC who received platinum-based chemotherapy plus bevacizumab, between January 2015 and December 2016. Patient characteristics, treatment details and adverse events were reviewed and analyzed in 2 settings: younger (<65 years, group 1) and elderly (≥65 years, group 2). A binary logistic model was applied to correlate clinical variables and severe (grade ≥3) toxicity risk.ResultsOverall, 283 patients with EOC were included, with 72 (25.4%) older patients compared with 211 (74.6%) younger women. Bevacizumab had been administered to 234 patients (82.7%) as first-line treatment and in 49 (17.3%) with recurrent disease. At diagnosis, elderly patients presented with at least one comorbidity and were taking at least 1 medication in 84.7% and 80.6% of the cases respectively, compared with correspondingly 47.4% and 37.4% in group 1 (p<0.001). Nonetheless, the occurrence of serious (grade ≥3) adverse events did not increase among the older group. Creatinine serum levels >1.1 g/dL, estimated glomerular filtration rate (eGFR) ≤60 mL/min, ≥3 comorbidities were independently associated with a higher severe toxicity.ConclusionsElderly patients with EOC can safely be treated with bevacizumab; factors other than age, as higher creatinine serum levels, eGFR and number of comorbidities should be considered to better estimate bevacizumab-related toxicity risk.

Weekly Paclitaxel and Carboplatin Plus Bevacizumab as First-Line Treatment of Metastatic Triple-Negative Breast Cancer. A Multicenter Phase II Trial by the Hellenic Oncology Research Group

BackgroundTriple-negative breast cancer (TNBC) lacks a standard targeted therapeutic strategy and is treated with conventional cytotoxic agents. Because of the sensitivity of TNBC to platinum compounds and the synergistic effect of bevacizumab with paclitaxel we investigated the efficacy and toxicity of weekly paclitaxel and carboplatin in combination with bevacizumab as first-line treatment in metastatic TNBC. Patients and MethodsThis phase II study followed the Simon’s 2-stage optimal design. Paclitaxel (90 mg/m2) and carboplatin (2 area under the curve) were administered on days 1, 8, and 15 every 4 weeks, preceded by bevacizumab 10 mg/kg on days 1 and 15. The primary end point was the objective response rate (ORR). The null hypothesis that the ORR is ≤ 40% could be rejected if the number of objective responses was ≥ 23 among 46 evaluable patients. ResultsA total of 46 patients were enrolled. Seven (15.2%) complete and 23 (50%) partial responses were observed for an ORR of 65.2% (95% confidence interval, 52.9%-80.4%). The median progression-free survival was 10.3 months, the median overall survival 25.7 months, and the median duration of response 18.2 months. Neutropenia Grade III and IV was experienced by 13 (28.3%) and 6 (13.04%) patients, respectively. One patient developed an uneventful Grade IV thrombocytopenia. There was 1 toxic death due to febrile neutropenia. Other Grade III toxicities included anemia (n = 2), neurotoxicity (n = 2), thrombocytopenia (n = 1), and diarrhea (n = 1). No serious bevacizumab-related toxicities were observed. ConclusionThe study achieved its primary end point by showing clinical activity for weekly paclitaxel with carboplatin and bevacizumab combination. This regimen merits further evaluation in this setting.

Optimizing bevacizumab dosing in glioblastoma: less is more.

Compared to traditional chemotherapies, where dose limiting toxicities represent the maximum possible dose, monoclonal antibody therapies are used at doses well below maximum tolerated dose. However, there has been little effort to ascertain whether there is a submaximal dose at which the efficacy/complication ratio is maximized. Thus, despite the general practice of using Bevacizumab (BEV) at dosages of 10mg/kg every other week for glioma patients, there has not been much prior work examining whether the relatively high complication rates reported with this agent can be decreased by lowering the dose without impairing efficacy. We assessed charts from 80 patients who received BEV for glioblastoma to survey the incidence of complications relative to BEV dose. All patients were treated with standard upfront chemoradiation. The toxicity was graded based on the NCI CTCAE, version 4.03. The rate of BEV serious related adverse events was 12.5% (n = 10/80). There were no serious adverse events (≥grade 3) when the administered dose was (<3mg/kg/week), compared to a 21% incidence in those who received higher doses (≥3mg/kg/week) (P < 0.01). Importantly, the three patient deaths attributable to BEV administration occurred in patients receiving higher doses. Patients who received lower doses also had a better survival rate, although this did not reach statistical significance [median OS 39 for low dose group vs. 17.3 for high dose group (P = 0.07)]. Lower rates of serious BEV related toxicities are noted when lower dosages are used without diminishing positive clinical impact. Further work aimed at optimizing BEV dosage is justified.

206P - Bevacizumab plus dose-dense neoadjuvant FEC followed by docetaxel chemotherapy in patients with HER2-negative breast cancer: a multicentre, phase 2 study by the Hellenic Oncology Research Group

Addition of bevacizumab to standard chemotherapy in the neoadjuvant setting improves the proportion of patients with HER2-negative breast cancer who achieve pathological complete response. We aimed to assess the addition of bevacizumab to dose-dense neoadjuvant chemotherapy. We enrolled women with operable HER2-negative breast cancer (T1c-T4 and N0-3). Patients underwent treatment every 2 weeks (with pegfilgrastim support) of fluorouracil (500 mg/m2), epirubicin (75 mg/m2), cyclophosphamide (500 mg/m2), and bevacizumab (10 mg/kg) for 4 cycles followed by docetaxel (75 mg/m2) and bevacizumab for 4 cycles. After surgery, patients received adjuvant radiotherapy, and hormone therapy (if indicated). The primary endpoint was pathological complete response in breast and the axilla, and safety of the combination. A two-stage trial design was planned with 15 and 33 patients to enroll, respectively. The trial was terminated early due to slow accrual and follow-up is ongoing. Between Oct, 2011, and Apr, 2015, we enrolled 34 patients, of whom 3 didn't undergo surgery, leaving 31 patients in the primary endpoint analysis. After neoadjuvant therapy, 5 (16.1%) of 31 patients achieved a pathological complete response according to centralized review. No patient discontinued treatment due to adverse events. The most frequent grade 3–4 toxicities were neutropenia (23.5%), nausea and vomiting (5,8%), and febrile neutropenia (2,9%). Only one patient developed grade III bevacizumab-related toxicity (hypertention). One patient died of pneumonia after cycle 8 and before surgery, which was thought to be unrelated to bevacizumab. After 25,2 months of median follow-up (range: 2,3-43,3) five patients experienced a disease relapse (16,1%). Our results seem to indicate that the addition of bevacizumab to dose-dense neoadjuvant chemotherapy with FEC and docetaxel, although safe and feasible, does not provide clinical benefit to patients with non-metastatic HER2-negative breast cancer. Translational research to identify patients who might benefit from bevacizumab is needed.

Safety, Effectiveness, and Costs of Bevacizumab-Based Therapy in Southern Spain: A Real World Experience.

To evaluate the safety and efficacy of bevacizumab in a broader patient population with solid tumors in the context of general clinical practice. Moreover, we quantified the economic impact and characterized the off-label use (OLU) of this agent in real-life prescribing practices.This is an open, retrospective, observational, real world study carried out at a regional Spanish hospital attending a population of 665,000 inhabitants. All of the patients receiving bevacizumab-containing therapy between January 2006 and February 2012 at the study hospital were included: no exclusion criteria were specified. All study variables were collected from available hospital records.The analysis comprised 240 episodes from 226 patients (male 41%; median age 57 years, 25% ≥65 years). Eighty cases (33%) of bevacizumab treatment were administered as first-line therapy. The median duration of bevacizumab treatment was 5.8 months (95% CI 5.1–6.6), without difference by age, line of treatment, or type of tumor. Typically bevacizumab-related toxicities included bleeding (25%), hypertension (5%), wound-healing complications (4%), gastrointestinal perforation (2%), and arterial thromboembolism (1%). Median progression-free survival was 7.5 months (95% CI 6.3–8.7) and median OS reached 13.1 months (95% CI 11.4–14.9). Bevacizumab increased the chemotherapy cost to 207% (from €3,115,615 to €9,552,405). Bevacizumab was prescribed off-label in 43% of episodes, amounting to €3,586,420 (56% of bevacizumab total cost).The efficacy and safety profile of bevacizumab in routine clinical practice is consistent with results observed in prospective randomized clinical trials. OLU of this drug should be closely monitored.

Bevacizumab toxicity in heavily pretreated recurrent epithelial ovarian, fallopian tube, and primary peritoneal cancers.

ObjectiveBevacizumab was recently approved by the US Food and Drug Administration for use in recurrent platinum resistant epithelial ovarian cancer (EOC), fallopian tube cancer (FTC), or primary peritoneal cancer (PPC) when no more than two prior cytotoxic regimens have been used; due to concerns for gastrointestinal perforation. We sought to determine bevacizumab-related toxicities in heavily pretreated recurrent EOC.MethodsWe performed a retrospective chart review of patients with recurrent EOC, FTC, and PPC from 2001 to 2011. Patients who received at least two prior chemotherapy regimens before bevacizumab were included. Medical records were reviewed for bevacizumab associated toxicities. The Wilcoxon-Mann-Whitney test was used to compare quantitative variables. Survival was estimated with the Kaplan-Meier method.ResultsSixty patients met inclusion criteria. At the start of bevacizumab treatment, the median age was 60 years and the median body mass index was 26.5 kg/m2. More than 50% of patients received bevacizumab after three prior cytotoxic regimens. Grade 3 or higher bevacizumab associated toxicity events occurred in four patients, including one patient who developed a rectovaginal fistula. The median overall survival from the start of bevacizumab treatment was 21.05 months (95% CI, 18.23 to 32.67; range, 1.9 to 110 months). The number of cytotoxic regimens prior to bevacizumab treatment did not differ in those that experienced a toxicity versus those that did not (p=0.66).ConclusionThe use of bevacizumab in heavily pretreated EOC, FTC, or PPC is worth consideration.

Clinical outcomes with bevacizumab-containing and non-bevacizumab-containing regimens in patients with recurrent glioblastoma from US community practices.

This analysis evaluated the efficacy and safety of bevacizumab as monotherapy and with irinotecan for recurrent glioblastoma in community-based practices. Adult patients with bevacizumab-naive, recurrent glioblastoma initiating second-line treatment (July 2006–June 2010) were identified using McKesson Specialty Health/US Oncology Network health records. Overall (OS) and progression-free survival (PFS) estimates were analyzed through July 2011 and compared for bevacizumab and non-bevacizumab regimens using the log-rank test. An adjusted Cox proportional hazards model assessed the effects of patient and treatment characteristics on outcomes. The analysis identified 159 patients initiating second-line treatment with a bevacizumab-monotherapy (n = 57), bevacizumab-combination (n = 79), or non-bevacizumab (n = 23) regimen. Patient characteristics were generally similar across groups. In the Cox analyses, OS (hazard ratio [HR] 0.51 [95 % confidence interval (CI) 0.31–0.82]; univariate medians: 8.86 vs. 5.19 months) was significantly longer with bevacizumab-containing regimens. Median PFS was longer with bevacizumab-containing regimens, but did not reach statistical significance (HR 0.64 [95 % CI 0.38–1.09]; univariate medians: 7.00 vs. 4.00 months). Analyses showed that each bevacizumab treatment group relative to non-bevacizumab had a reduced risk of death (bevacizumab-monotherapy regimen: HR 0.56 [95 % CI 0.31–1.03] and bevacizumab-combination regimen: HR 0.34 [95 % CI 0.21–0.68]). Patients receiving the bevacizumab-combination regimen trended toward longer OS and PFS than those receiving the bevacizumab-monotherapy regimen. Rates of bevacizumab-related toxicities were consistent with clinical trial reports.Electronic supplementary materialThe online version of this article (doi:10.1007/s11060-015-1752-y) contains supplementary material, which is available to authorized users.

Practical management of bevacizumab-related toxicities in glioblastoma.

Bevacizumab, currently an option for treatment of different types of tumors including glioblastoma, has a peculiar toxicity profile related to its antiangiogenic effect. Because some bevacizumab-related adverse events can be life threatening, it is important to identify risk factors and to establish treatment protocols to minimize treatment-related morbidity and mortality. In glioblastoma patients, the risk of developing certain side effects, such as gastrointestinal perforation, venous thromboembolism, and intracranial hemorrhages, is slightly higher than in patients treated with bevacizumab for other tumor types. We performed a systematic review of the side effects of bevacizumab and their incidence, causal mechanisms, and available treatments. Finally, we identified risk factors and proposed preventive and therapeutic measures for these adverse events.

AI-01 * ARE WE USING TOO MUCH BEVACIZUMAB IN OUR GBM PATIENTS?

INTRODUCTION: Compared to traditional chemotherapies, where dose limiting toxicities represent the maximum possible dose, monoclonal antibody therapies are used at doses well below MTD. However, there has been little effort to ascertain whether there is a submaximal dose at which the efficacy/complication ratio is maximized. Thus, despite the general practice of using Bevacizumab (BEV) at dosages of at least 10mg/kg every other week (5mg/week), there has not been any study to our knowledge that this is optimal in terms of minimizing side effects. METHODS: We assessed charts from 59 patients treated at Stanford who received BEV for glioblastoma to survey the incidence of complications relative to the dose of medication/week. All patients were treated with standard upfront chemoradiation. The BEV dose was calculated per week. The toxicity was graded based on the NCI CTCAE, version 4.03. RESULTS: 52 patients received BEV for progression; the others received it as an added upfront treatment to control mass effect during irradiation. The median overall survival was 15 months (2-87). The dose ranged from 1.6 to 10/mg/kg/week with a median of 3.3mg/kg/week. The rate of BEV serious related adverse events was 13.5% (n = 8/59). Compared to a 20% incidence of Grade 3 toxicities in patients receiving > 3.0mg/kg/wk (8/40), no toxicity was seen in patients administered lower doses (0/19), (P 5mg/kg/week. No differences in survival were noted as a function of dose. CONCLUSION: Lower rates of serious BEV related toxicities are noted when lower dosages are used. Furthermore, besides these findings being clinically significant, there is also an added economic benefit to using lower amounts of this very expensive medicine. Further work aimed at optimizing BEV dosage is justified.

Bevacizumab-related toxicities in the National Cancer Institute malignant glioma trial cohort.

Bevacizumab is an antiangiogenic agent approved for recurrent glioblastoma due to high response rates. Prior reviews focused on severe or cardiovascular bevacizumab toxicities. We performed a comprehensive review of toxicities experienced among 210 patients enrolled in 3 phase II bevacizumab trials for recurrent malignant gliomas at the National Cancer Institute. No bevacizumab toxicities were experienced by 20 % patients, 40.2 % on monotherapy versus ≤9.5 % on combination therapy. Hypertension and proteinuria occurred in ~25 %. Fatigue, hypophosphatemia, aspartate aminotransferase elevation, rashes were common. Low grade headache, hoarseness, myalgias/arthralgias, liver enzyme elevation, azotemia and electrolyte abnormalities were noted. Rare severe toxicities, including thrombosis, hemorrhage, wound complications and colonic perforations, occurred at rates seen in other diseases. Leukopenia and neutropenia occurred solely with combination therapy, while thrombocytopenia occurred in 12.5 % on bevacizumab monotherapy. Thrombocytopenia was generally mild, but severe in (1.4 %) and increased in frequency with prolonged or combination therapy. Bevacizumab-related deaths occurred in 4 (1.9 %) patients, including brain ischemia (n = 1) and sudden unexplained deaths (n = 2). Prior hypertension increased the odds of hypertension by ≥3.4-fold (p < 0.001) and grade 3+ hypertension by ≥11.2 (p < 0.001). Prior hypertension increased the odds of hypophosphatemia by 2.4-fold (p = 0.011), but failed to predict proteinuria or azotemia. Age did not greatly impact toxicity. Hypertension, proteinuria and hypophosphatemia often occurred concurrently, more frequently and severely with prolonged use. Our study shows bevacizumab monotherapy is well tolerated, but toxicity increases with combination therapy. Balancing the risks and benefits of bevacizumab requires understanding the spectrum of bevacizumab toxicities and predisposing factors.

Efficacy and safety of bevacizumab in elderly patients with metastatic colorectal cancer: results from the Czech population-based registry

BackgroundPatients aged 65 years and older represent the majority of patients with metastatic colorectal cancer (mCRC). However, this patient population is often underrepresented in clinical trials and probably undertreated in the clinical practice.MethodsWe have analysed the outcomes of 3,187 mCRC patients treated with first-line bevacizumab based on data from the Czech national registry of mCRC patients aiming to compare the treatment efficacy and safety according to the age categories.ResultsIn total, 2,126 (66.7%), 932 (29.2%), and 129 (4.0%) patients were aged <65 years, 65 to 75 years, and 75+ years, respectively. Median progression-free survival (PFS) was 11.4, 11.3, and 11.8 months for patients aged <65 years, 65 to 75 years, and 75+ years, respectively (p = 0.94). Median overall survival (OS) was 26.9, 27.5, and 25.1 months for patients aged <65 years, 65 to 75 years, and 75+ years, respectively (p = 0.73). Using multivariable Cox model for both PFS and OS, the patient age was not significantly associated with either PFS or OS. No increase in bevacizumab-related toxicity was observed among the elderly mCRC patients with the exception of hypertension, which was observed in 71 (3.3%), 34 (3.6%), and 10 (7.8%) patients aged <65 years, 65 to 75 years, and 75+ years, respectively.ConclusionsThe results of the present study suggest similar outcome in terms of OS and PFS with bevacizumab-containing therapy in elderly mCRC patients fit for chemotherapy combined with targeted therapy compared to younger patients. Thus, chronological age should not be considered to represent a limitation in prescribing bevacizumab-containing therapy in mCRC patients.

Bevacizumab in Combination with FOLFIRI in the First-Line Treatment of Patients with Advanced Colorectal Cancer: A Single-Institution Experience

Introduction: Bevacizumab combined with IFL (irinotecan, bolus 5-fluorouracil, and leucovorin) has been shown to improve outcomes for patients with metastatic colorectal cancer (mCRC). However, infusional 5-fluorouracil-based combinations are now considered optimal in this setting. We analyzed the efficacy and toxicity of FOLFIRI (irinotecan, infusional 5-fluorouracil, and leucovorin)-bevacizumab in an unselected cohort of consecutive patients with mCRC. Materials and Methods: Patients with unresectable mCRC received bevacizumab 5 mg/kg and irinotecan 180 mg/m² on day 1, leucovorin 200 mg/m² on days 1 and 2, 5-fluorouracil 400 mg/m² bolus, and 600 mg/m² continuous infusion on days 1 and 2, every 14 days. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and safety were assessed. Results: Overall, 127 patients were included (69% male, median age 64 years); 15 patients had diabetes, 40 had hypertension, and 23 were undergoing anticoagulant/antiplatelet therapy. Median PFS was 11.0 months (95% CI 10.0-12.0); median OS was 26.0 months (95% CI 21.9-30.1). The ORR was 55.1% (95% CI 46.3-63.6%), with 12 complete responses, 58 partial responses, and 44 patients with stable disease. Salvage surgery was performed in 31 patients (24%), including 23 with liver metastases and one with lung metastases. Grade 3/4 toxicities included neutropenia (17%), vomiting (6%), and diarrhea (17%); grade 3/4 bevacizumab-related toxicities included hypertension (2%), hemorrhage (2%), and venous (7%) and arterial thromboembolic events (5%). Conclusion: FOLFIRI-bevacizumab was active and tolerable in this cohort of unselected patients with mCRC, resulting in a high surgical rescue rate and prolonged survival.

Outcomes for Women Receiving Bevacizumab for Treatment of Ovarian Cancer Versus Other Solid Tumors at an Academic Oncology Center

BackgroundThe main objective of this study was to determine the incidence of severe toxicity associated with bevacizumab use in women with ovarian cancer compared with that in women with other solid tumors. Patients and MethodsThis retrospective cohort study was performed by evaluating women treated with single-agent or combination bevacizumab in the Program in Women's Oncology between January 2004 and May 2009. Data was collected from electronic and office-based medical records. Toxicity was assessed according to the National Cancer Institute's Common Toxicity Criteria version 3.0 guidelines. A total of 103 women were treated with bevacizumab: 41 women (40%) with ovarian cancer and 62 (60%) with other solid tumors. ResultsThere was no increase in the number of toxic effects seen in patients treated for ovarian cancer versus other tumor types. However, GI perforations were seen in 7.3% of women with ovarian cancer, whereas none were seen in those treated for other cancers (P = .06). More than 1 bevacizumab-related toxic effect (hazard ratio [HR], 2.74; 95% CI, 1.35-5.55) and treatment with bevacizumab after 3 prior lines of chemotherapy (HR, 2.44; 95% CI, 1.159-5.129) were associated with an increase in mortality in women with ovarian cancer. We found no significant difference in the incidence of bevacizumab-related toxicities when comparing ovarian cancer to other cancers. However, ovarian cancer patients did appear to have a statistically nonsignificant higher percentage of GI perforations. ConclusionFurther studies evaluating patient factors associated with increased risk of toxicities may be warranted to assist with appropriate patient selection prior to bevacizumab use.

Neoadjuvant Oxaliplatin and Capecitabine and Bevacizumab without Radiotherapy for Poor-risk Rectal Cancer: N-SOG 03 Phase II Trial

This Phase II trial was designed to evaluate the safety and efficacy of neoadjuvant oxaliplatin and capecitabine and bevacizumab without radiotherapy in patients with poor-risk rectal cancer. Patients with magnetic resonance imaging-defined poor-risk rectal cancer received neoadjuvant oxaliplatin and capecitabine and bevacizumab followed by total mesorectal excision or more extensive surgery. Between February 2010 and December 2011, 32 patients were enrolled in this study. The completion rate of the scheduled chemotherapy was 91%. Reasons for withdrawal were refusal to continue therapy in two patients and disease progression in one, with two of these three patients not undergoing surgery. Among the 29 patients who completed the scheduled chemotherapy, one refused surgery within 8 weeks after the completion of chemotherapy, which was the period stipulated by the protocol, and another had rectal perforation, requiring urgent laparotomy. As a result, the completion rate of this experimental treatment was 84%. Of the 30 patients who underwent surgery, the R0 resection rate was 90% and a postoperative complication occurred in 43%. A pathological complete response was observed in 13% and good tumor regression was exhibited in 37%. Neoadjuvant oxaliplatin and capecitabine plus bevacizumab for poor-risk rectal cancer caused a high rate of anastomotic leakage and experienced a case with perforation during chemotherapy, both of which were bevacizumab-related toxicity. Although the short-term results with the completion rate of 84.4% and the pathological complete response rate of 13.3% were satisfactory, we have to reconsider the necessity of bevacizumab in neoadjuvant chemotherapy (UMIN number, 000003507).

Efficacy and safety of bevacizumab (BEV) plus chemotherapeutic agents in the treatment of metastatic colorectal cancer, mCRC

To assess the efficacy and safety of bevacizumab (BEV) plus chemotherapeutic agents in the treatment of metastatic colorectal cancer (mCRC). Seventy-seven mCRC patients received BEV plus 5-Fu type, oxaliplatin or irinotecan-based chemotherapy. The clinical efficacy and bevacizumab-related adverse reactions were observed. The efficacy assessment was conducted after at least 2 cycles of BEV therapy. The adverse reactions were recorded in each therapy cycle. Among the 77 cases, 64 patients had finished the efficacy assessment. The adverse reactions in all patients were assessed. The overall response rate (ORR) of BEV plus chemotherapy regimen was 18.75% (12/64), and the disease control rate (DCR) was 75.0% (48/64). In 27 patients who received the regimen as first-line treatment, the ORR reached 37.0% (10/27), while the DCR was 85.2%. Four patients with potentially resectable lesions became resectable after the regimen and received R0 resection of the liver metastases successfully. Twenty-five patients who received the regimen as second line therapy had poor result with ORR 8.0% and DCR 76.0%. Hypertension was observed in 12 cases, with 8 cases of grade 1, 3 cases of grade 2, 1 case of grade 3. Various bleedings occurred in 24/77 cases (31.2%), all were of grade 1-2, including 17 cases of epistaxis, grade 1 hemorrhoid bleeding in one case, hematuria in 3 case (2 of grade 1, 1 of grade 2), GI bleeding in 2 cases, hemoptysis in 1 case (grade 2), and proteinuria in 4 cases (grade 1). Intestinal perforation occurred in 1 case (0.3%). In two patients who had incomplete intestinal obstruction history appeared exacerbated intestinal obstruction symptoms after the application of BEV plus CPT11 regimen. BEV plus chemotherapy regimen as first-line treatment can improve the ORR and DCR of mCRC patients. When it was used as second- or later-line therapy, it may display satisfied DCR, although with a poor efficacy. The bevacizumab-related toxicity is mild and can be well tolerated.