DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

aflibercept (VEGF Trap), a recombinant molecule that
utilizes the VEGFR1-binding domain to sequester
VEGF, acts as a “soluble decoy receptor” for VEGF.
Alternatively, the propagation of pro-angiogenic
signals can be abrogated by the inhibition of the tyrosine
kinase activity of VEGFR. Three small molecules
(pazopanib, sorafenib, and sunitinib) that inhibit the
kinase function of VEGFR-2 have been approved for
clinical use. Although bevacizumab and the small molecules
share a similar spectrum of toxicities, they have
somewhat different spectra of clinical activity and significant
differences in pharmacokinetics.
Bevacizumab. Bevacizumab (AVASTIN), a humanized
antibody directed against VEGF-A, was the first FDAapproved
molecule that specifically targeted angiogenesis.
As a single agent, it delays progression of
renal-cell cancer, and, in combination with cytotoxic
chemotherapy, effectively treats lung, colorectal, and
breast cancers.
In clear-cell renal-cell carcinoma, a cancer notoriously resistant
to traditional chemotherapeutic agents, single-agent bevacizumab
increases survival by 3 months (Yang et al., 2003). Clear-cell renalcell
cancer, a highly vascular tumor, presents a particularly attractive
target for bevacizumab and other anti-angiogenic agents because
mutations or DNA methylation affecting the von Hippel-Lindau
(VHL) gene are a constant feature of renal-cell carcinomas. The VHL
gene product functions as an inhibitor of the angiogenic pathway.
Thus, a loss of VHL protein activates hypoxia inducible factor 2
(HIF-2), a transcription factor that promotes synthesis of VEGF and
other hypoxic response proteins. In 2009, the FDA approved bevacizumab
in combination with interferon-α for the treatment of
metastatic renal-cell carcinoma.
Bevacizumab is approved as a single agent following prior
therapy for glioblastoma. In all other cancers, bevacizumab has little
apparent single-agent activity but improves survival in epithelial
cancers in combination with standard chemotherapeutic agents
(Sandler et al., 2006). Bevacizumab with carboplatin and paclitaxel
increases survival in non–small lung cancer by 2 months. Likewise,
bevacizumab combined with FOLFOX (5-FU, leucovorin, and
oxaliplatin) or FOLFIRI (5-FU, leucovorin, and irinotecan)
improves survival by 5 months in metastatic colon cancer. Finally, the
combination of bevacizumab with docetaxel increases progressionfree
survival in patients with metastatic breast cancer (Miller et al.,
2007). Trials testing bevacizumab in glioblastoma multiforme have
yielded promising results with minimal evidence of intracranial
hemorrhage.
Clinical uses of bevacizumab now have expanded beyond the
realm of oncology. In wet age-related macular degeneration, abnormal
choroidal neovascularization often leads to rapid visual loss.
A slightly altered version of bevacizumab called ranibizumab
(LUCENTIS), in which the Fc region has been deleted, effectively treats
wet macular degeneration. Bevacizumab restores hearing in patients
with progressive deafness due to neurofibromatosis type 2–related
tumors (Plotkin et al., 2009).
Clinical Pharmacology. Bevacizumab is administered intravenously
as a 30- to 90-minute infusion. In metastatic colon cancer, in conjunction
with combination chemotherapy, the dose of bevacizumab
is 5 mg/kg every 2 weeks. In metastatic non–small cell lung cancer,
doses of 15 mg/kg are given every 3 weeks with chemotherapy. For
treatment of metastatic breast cancer, patients receive 10 mg/kg of
bevacizumab every 2 weeks in combination with paclitaxel or docetaxel.
The differing doses of bevacizumab reflect the varying
designs of approval-directed trials. The optimal dosage in each case
has not yet been defined. The antibody has a plasma t 1/2
of 4 weeks.
Toxicity. Bevacizumab causes a wide range of class-related adverse
effects. A prominent concern with this class of agents was the
potential for vessel injury and bleeding, noticed in patients with
squamous-cell lung cancer (Johnson et al., 2004). Bevacizumab is
contraindicated for patients who have a history of hemoptysis, brain
metastasis, or a bleeding diathesis, but in appropriately selected
patients, the rate of life-threatening pulmonary hemorrhage is <2%
(Sandler et al., 2006).
The safety of operating on patients treated with bevacizumab
continues to be a major concern because of the risk of bleeding and
poor wound healing. In a pooled analysis of two large clinical trials
of colon cancer, patients who needed surgery while being treated
with bevacizumab had a higher rate (13% versus 3.4%) of serious
wound healing complications than patients treated with placebo
(Scappaticci et al., 2007). In light of these data and because of the
long t 1/2
of bevacizumab, elective surgery should be delayed for at
least 4 weeks from the last dose of antibody, and treatment should be
not resumed for at least 4 weeks after surgery.
Other toxicities characteristic of anti-angiogenic drugs
include hypertension and proteinuria. A majority of patients receiving
the drug require antihypertensive therapy, particularly those
receiving higher doses and more prolonged treatment (Sandler et al.,
2006; Hurwitz et al., 2004; Miller et al., 2007). The mechanism driving
this hypertension is still unclear but may relate, in part, to
decreased endothelial nitric oxide production. Physicians should
carefully monitor the blood pressure of all patients on bevacizumab
and intervene with antihypertensives when appropriate. Case reports
describe patients with poorly controlled hypertension developing a
reversible posterior leukoencephalopathy during bevacizumab
treatment. Bevacizumab also is rarely associated with congestive
heart failure, probably secondary to hypertension (Miller et al., 2007).
Patients often develop proteinuria during bevacizumab treatment,
but it usually is an asymptomatic finding and rarely associated
with nephrotic syndrome (Gressett and Shah, 2009).
The most dreaded vascular toxicity of anti-angiogenic agents
is an arterial thromboembolic event (i.e., stroke or myocardial infarction).
A meta-analysis found that the rate of arterial thromboembolic
events in patients receiving bevacizumab-containing regimens
reached 3.8% compared to the control rate of 1.7% (Scappaticci
et al., 2007). To reduce the risk of arterial thromboembolic events,
clinicians should carefully evaluate a patient’s risk factors (age
>65 years, clotting diathesis, a past history of arterial thromboembolic
events) before starting the drug.
GI perforation, a potentially life-threatening complication of
bevacizumab, has been observed with particular frequency (up to
11%) in patients with ovarian cancer, perhaps related to the presence
of peritoneal carcinomatosis and to prior abdominal surgery.
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CHAPTER 62
TARGETED THERAPIES: TYROSINE KINASE INHIBITORS, MONOCLONAL ANTIBODIES, AND CYTOKINES