Bevacizumab (Avastin)

Human monoclonal antibody against vascular endothelial growth factor (VEGF).

It is a cytokine, secreted by multiple different types of cells in the body with roles in development, hematopoiesis, and wound healing.

Binds and effectively neutralizes circulating VEGF.

Binds specifically to VEGF-A ligand, a glycoprotein of the VEGF family.

Vascular endothelial growth factor-A binds to tyrosine kinase receptors flt-1 (VEGFR-1) and to flk-1/KDR (VEGFR-2) which serve as a primary mediator of angiogenesis.

Binding of Bevacizumab to VEGF prevents interaction of VEGF receptors on the cell surface inhibiting angiogenesis and other pathways.

The combination of bevacizumab plus nirapib in women with relapsed platinum sensitive epithelial ovarian cancer had an objective response rate of 45%.

May induce antiangiogenesis, normalize tumor vasculature, reduce the number of endothelial progenitor cells and decrease the number of circulating endothelial cells.

VE,GF secreted by tumor cells and tumor associated macrophages can lead to neoangiogenesis, proliferation, and metastases through its effects on endothelial cells

Theorized to block VEGF attachment to endothelial cells to prevent the growth of new vessels and the spread of cancer.

May help remodel tumor vasculature allowing increased penetration of chemotherapy drugs.

First and second line bevacizumab plus chemotherapy improves progression free survival and overall survival in patients with advanced colorectal cancer or metastatic colon cancer compared to chemotherapy alone.

Associated with hypertension in 30-40% of patients but severe grade 3-5 hypertension noted in 3-8%.

Hypertension associated with single nucleotide polymorphisms associated with the renin-angiotensin-aldosterone system, sodium regulation, and bradykinin receptor.

Can result in gastrointestinal perforation and wound dehiscence.

Sometimes associated with intra-abdominal abscess.

Serious and fatal hemoptysis reported in non-small cell cancer of the lung.

Reported to cause hypertension crisis, nephrotic syndrome, congestive heart failure.

Impairs wound healing and should be withheld until 4 weeks after major surgery.

May result in ovarian failure, infertility and osteonecrosis of the jaw.

It is associated with nasal septum perforation.

Dosage 5mg/kg and 10mg/kg, with most studies showing lower dose to be as effective as higher dosage.

First dose usually given over 90 minutes, second dose given over 60 minutes and subsequent treatments given over 30 minutes: recent studies suggest 5 mg/kg can be given safely over 10 minutes with safety.

Most common adverse events are asthenia, pain, abdominal pain, headache, hypertension, diarrhea, nausea, vomiting, anorexia, stomatitis, proteinuria, constipation, dyspnea, epistaxis, impaired wound healing, dermatitis, gastrointestinal perforation, hemorrhage, and arterial thromboembolism.

Rarely can cause acute liver injury.

Fever, chills and rash occasional occurrences.

Increased risk for serious arterial thromboembolic events including stroke, myocardial infarctions, transient ischemic attacks and angina.

Does not have any overlapping hematologic or gastrointestinal toxicities with chemotherapy agents.

Phase 3 and 4 trials have indicated associated adverse effects of grade 3/4 hypertension 1- 18%, proteinuria grade 3, 0-2%, bleeding grade 3/4 less than 1-6%, GI perforation 0-2%, wound healing complications 1%, arterial thromboembolism less than 1-2%, bleeding grade 3/4 less than 1%-6%.

Serious and sometimes fatal GI perforation occurs at up to 2.4%i compared to controls.

The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in treated patients.

The drug should be discontinued at least 28 days prior to elective surgery, and should not be initiated for at least 28 days after surgery and until the surgical wound is fully healed.

Severe or fatal hemorrhage, hemoptysis, GI bleeding, CNS hemorrhage, and vaginal bleeding are increased.

In patients with tumors near the central airway, use of antiangiogenic agents has been linked to fatal hemorrhage after stereotactic body radiation therapy.

The drug should not be administered in patients with serious hemorrhage or recent hemoptysis.

Pre-existing hypertension does not predispose patients to hypertensive adverse effects.

No deaths have been reported from hypertension, but more than 1% of patients discontinue this drug because of hypertension.

Grade 4 hypertension is rare, and blood pressure can typically be controlled with a single antihypertension agent.

Nephrotic syndrome has been reported in 5 of 1032 patients treated with bevacizumab from pooled data.

Reported incidence of venous thromboembolism in patients treated with this agent varied from 3-19% in phase 2 and 3 randomized controlled trials.

In a phase 2 trial (PASSPORT) trial for first and second line treatments of non-squamous cell lung cancer with previously treated brain metastases received bevacizumab with platinum or other single agent chemotherapy: There was no increase in CNS hemorrhage indicating that bevacizumab was a safe agent to be administered in patients with treated brain metastases (Socinski MA).

In a phase II study of bevacizumab and chemotherapy fatal hemorrhage was related to central cavitating lung lesions, and this is more frequent in squamous cell cancers (Johnson DH).

In a meta-analysis of 7956 patients with a variety of malignancy in 15 randomized clinical studies revealed high grade thromboembolism to occur in 11.9% of patients given this agent, which was a relative risk of 1.33 (Nalluri SR).

In a pooled analysis of 1745 patients treated with this agent for metastatic colorectal cancer, breast cancer or NSCLC indicated the in combination with chemotherapy there was not an increased risk of venous thromboembolism when compared to chemotherapy alone (Scappiticci FA).

Posterior leukoencephalopathy syndrome, a brain capillary leak syndrome associated with hypertension, edema, and cytotoxic effects on vascular endothelium, reported in 0.1% of cases.

Reversible posterior leukoencephalopathy associated with headaches, seizures, visual impairment and altered mental status.

When added to first line chemotherapy in metastastic colon cancer with Irinotecan and 5FU/leucovorin results in 34% reduction in risk of death, improved response rate of 44% vs. 34.8%, increase in progression free survival 10.6 months vs 6.2 months, and increase in median duration of response 10.4 months vs. 7.1 months, compared to the same chemotherapy alone.

Irinotecan, 5-FU/ leucovorin vs. irinotecan, 5FU/leucovorin plus Bevacizumab in metastases colorectal cancer resulted in a survival improvement of 30%, with survival of 15.6 months and 20.3 months, respectively.

Trials have established efficacy of the addition of bevacizumab to first line chemotherapy in metastatic colorectal cancer.

Among patients with refractory metastatic, colorectal cancer, treatment with trfluridine-tipiracil and bevacizumab, resulted in longer overall survival than trifluridine-tipiracil alone(10.8 vs 7.3 months)

In randomized trials the benefits of bevacizumab is observed irrespective of KRAS mutational status.

As a single agent in second or third-line treatment for ovarian cancer there was a 17.8% objective response rate and 38.7% 6 months progression free survival rate and a median progression free survival of 4.8 months in a study by the Gynecologic Oncology Group (GOG).

Three Regimens of Eloxatin Evaluation (TREE-2 study) evaluated the safety and efficacy of three oxaliplatin and fluoropyrimidine regimens, with or without bevacizumab in metastatic colorectal cancer-indicating that the addition of bevacizumab was well tolerated without markedly changing overall toxicity.

The TREE-2 study compared Oxaliplatin with fluoropyrimidine given as a continuous infusion, bolus or oral treatments with or without bevacizumab: overall response rates, time to progression and overall survival were improved over the same treatments without bevacizumab.

TREE-2 study revealed a median overall survival of previously untreated patients with metastatic colorectal cancer and oxaliplatin and fluoropyrimidine and bevacizumab to have a median overall survival of approximately 2 years.

Phase II study of cyclophosphamide with bevacizumab had a partial response rate of 28% and disease stabilization of 59% with median progression free survival of 5.8 months among 29 evaluable patients with recurrent ovarian cancer in a California Cancer Consortium Trial.

Bevacizumab during and up to 10 months after carboplatin and paclitaxel chemotherapy prolongs median progression free survival by about four months in advanced ovarian cancer (Burger RA et al).

Use in NSCLC with chemotherapy significantly increases response rate, progression free survival, and median survival compared to chemotherapy treatment alone.

The addition of bevacizumab to adjuvant chemotherapy does not improve overall survival for patients with surgically resected early non-small cell lung cancer and does not have a role in this setting (Wakelee HA).

E1505 trial showed no overall survival nor disease-free survival improvement with the addition to chemotherapy for non squamous non-small cell lung cancer.

AVOREN trial of 649 randomized metastatic renal cancer patients to Interferon-alpha with placebo or bevacizumab 10 mg/kg every 2 weeks: progressive free survival in the combination group 10.2 months vs. 5.4 months for the Interferon-placebo group, response rate 30.6% vs. 12.4% for the interferon-placebo group with a trend toward improved overall survival as well.

In combination with paclitaxel (Taxol) there is an improved progression free survival in patients with previously untreated metastatic breast cancer (Miller K).

Therapeutic benefit when used in combination chemotherapy in breast cancer.

Addition of bevacizumab to chemotherapy agents paclitaxel, nab-paclitaxel, docetaxel, gemcitabine capecitabine or vinorelbine in seoond line breast cancer vs the addition of placebo: 684 patients progresion free survival with the bevacizumab group was 7.2 months vs 5.1 months for placebo group, overall response rate 39.5% vs 29.6%, median overall survival 18 months vs 16.4 months in the placebo plus chemotherapy group (Brufsky A).

Bevacizumab and anti-metabolites capecitabine and gemcitabine improve the outcomes when added to taxanes in patients with metastatic breast cancer.

Incorporation of bevacizumab into sequential anthracycline- and taxane-containing adjuvant therapy does not improve IDFS or overall survival in patients with high-risk human epidermal growth factor receptor 2–negative breast cancer (Miller KD).

In a randomized study of 1206 patients to receive neoadjuvant therapy consisting of docetaxel, docetaxel plus capecitabine or docetaxel plus gemcitabine for 4 cycles, with all regimens followed by treatment with doxorubicin-cyclophosphamide for 4 cycles: patients were randomly assigned to receive or not receive bevacizumab for the 1st 6 cycles of chemotherapy.-The addition of bevacizumab significantly increased the rate of pathological complete response from 28.2% without the drug and 34.5% with it (Bear HD et al).

Bevacizumab and chemotherapy increases progression free survival, response rates, but not overall survival, and prospective, randomized trials for metastatic breast cancer.

Study AVF3708g bevacizumab at 10mg/kg IV alone or with irinotecan in previously treated Glioblastoma multiforme patients that failed radiotherapy with temozolomide resulted in a 25.9% objective response with a median response duration of 4.2 months (Kreisl TN).

NCI 06-C-0064E study of bevacizumab in Glioblastoma multiforme patients that failed temozolomide and radiotherapy resulted in a 19.6% objective response rate with a median response duration of 3.9 months.

Bevacizumab for recurrent grade 2 and grade 3 gliomas is ineffective(van den Bent).

Adding bevacizumab to R-CHOP was associated with increased risk of LV ejection fraction and congestive heart failure in patients with diffuse large B cell lymphoma (The MAIN Study).

In the above study the risk of congestive heart failure was greater in patients 65 years and older, and it increased the rate of doxorubicin associating cardiac adverse events: the addition of bevacizumab should not be used in conjunction with R-CHOP for the treatment of DLBCL.

Squamous cell histology associated with increased risk of severe hemoptysis.

Most cases of pulmonary hemorrhage occurred shortly after initiation of therapy in patients with squamous cell lung cancer.

Drug usually administered over 90 minutes for the first infusion, 60 minutes for the second infusion and all subsequent infusions can be given over 30 minutes.

At the 15 mg/kg dose a 0.5mg/kg/min can be administered over 30 minutes with safety and a 5mg/kg dose can be administered at the same rate, that is, over 10 minutes with a few clinically minor events.

Shortening length of infusion time is safe and is without an excessive risk of hypersensitivity reactions. It is invasive well very good and we we can

Infusion reactions may include nausea, vomiting, hypoxia, flushing, urticarial rash and chills.

In combination with doxorubicin may potentiate cardiac toxicity.

In a meta-analysis of randomized controlled studies bevacizumab in combination with chemotherapy or biological therapy, compared to chemotherapy alone, is associated with increased treatmenr related mortality (Ranpura V et al).

The use of taxanes and cisplatin in combination may increase the risk of fatal adverse reactions, as may use in prostate and lung cancer (Ranpura V et al).

Most common fatal adverse events are hemorrhage (23.5%), neutropenia with lethal infection (12,2%), gastrointestinal perforation (7.1%), pulmonary embolism (5.1%), and cerebrovascular accidents (5.1%) (Ranpura V et al).

Higher doses not associated with increase risk of fatal adverse events.

Capecitabine with or without bevacizumab (phase 2 trial) doubled response rates in metastatic breast cancer patients in patients treated with bevacizumab, but no difference in progression free or overall survival (Miller KD et al).

Paclitaxel with bevacizumab increased response rates and doubled time to progression in metastatic breast cancer(Miller K et al).

AVEREL phase III trial the addition of Bevacizumab in combination with Herceptin/Docetaxel in patients with HER-2 positive metastatic breast cancer did not improve PFS.

GOG240 compared paclitaxel and cisplatin or Topotecan with or without bevacizumab in patients with stage IV-B, recurrent or persistent cervical cancer: Revealed patients randomized to the bevacizumab arms lived a median of 17 months and those in the regimen without this drug lived a median of 13 months.

The phase III Gynecology Oncology Group (GOG) 240 trial showed addition of bevacizumab (Avastin) to standard chemotherapy improved overall survival (OS) by nearly 4 months in women with advanced or relapsed cervical cancer (Krishnansu S. Tewari et al).

Administering bevacizumab with chemotherapy also yielded a 12% improvement in tumor response rate compared with chemotherapy alone.

Median progression-free survival (PFS) and overall response rate were also notably improved, and benefit with the addition of bevacizumab to treatment was seen even in women who had received pelvic irradiation.

The response rate in patients treated with chemotherapy alone was 36%, compared with a 48% response rate in patients treated with chemotherapy plus bevacizumab.

The addition of bevacizumab to platin based therapy in metastatic head and neck cancer does not improve overall survival, but does improve progression free survival.

An effective treatment for patients with severe anemia related to epistaxis and gastrointestinal bleeding in hereditary hemorrhagic telangiectasia.

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