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2 Journal of Oncology

conventional cytotoxic agents that target VEGF have taken

center stage.

Agents targeting angiogenesis include monoclonal anti-

bodies to the VEGF ligand [7–19], small tyrosine kinase

inhibitors that target the vascular endothelial growth factor

receptor [20–25], and soluble decoy VEGF receptors [39, 40].

The most studied agent to date has been bevacizumab, a

recombinant humanized monoclonal antibody to the VEGF

ligand.

To date several investigators [7–19](Ta bl e 1 )have

explored bevacizumab as a single agent or in combination

with chemotherapy in the management of advanced ovarian

cancer.

Several studies in both the upfront and in the recurrent

setting are underway. GOG 218 is a randomized placebo

controlled three-arm study examining the role of beva-

cizumab in combination with carboplatin and paclitaxel

and also as a maintenance therapy. ICON-7 is a two arm

trial comparing carboplatin and paclitaxel (six cycles) versus

carboplatin, paclitaxel, and bevacizumab (7.5 mg/kg) for six

cycles followed by 12 cycles of maintenance bevacizumab.

Campos et al. [20] is conducting a phase II trial of carbo-

platin/paclitaxel/bevacizumab in optimally and suboptimally

debulked patients. Patients achieving a clinical complete

response, partial response, or stable disease are subsequently

randomized to either bevacizumab for 12 months or the

combination of bevacizumab and erlotinib. Preliminary

safety results have noted an increase in hypertension but to

date no evidence of gastrointestinal perforations.

Given the recent data that has emerged on the role

on intraperitoneal chemotherapy [41–43]investigatorsare

exploring the role of IP chemotherapy with IV bevacizumab.

Several abstracts were highlighted at the recent American

Society of Clinical Oncology meeting. Konner et al. [44]

and McKeekin et al. [45] in independent studies reported

the feasibility of utilizing bevacizumab (IV) in conjunction

with intraperitoneal therapy. One bowel perforation [44]was

noted the Konner study while McKeekin et al. [45] colleagues

noted one deep venous thrombosis and one ﬁstula.

In the recurrent setting several trials are being con-

ducted. The OCEANS trial is a randomized study of

carboplatin/gemcitabine and bevacizumab (NCT 00434642)

versus carboplatin/gemcitabine. GOG 213 (Figure 1)isran-

domized trial in recurrent ovarian cancer patients. Patients

are stratiﬁed as to whether or not they are surgical candi-

dates. If the patients are deemed to be surgical candidates

they are randomized to surgery or no surgery followed

by randomization to chemotherapy. If patients are ran-

domized to no surgery they are subsequently randomized

to carboplatin and paclitaxel or carboplatin/paclitaxel and

bevacizumab.

The combination of carboplatin/DOXIL and beva-

cizumab is also being studied. The later trial may prove

to be intriguing given the recently reported results of the

CALYPSO trial [46]. In the CALYPSO trial the combina-

tion of Carboplatin-Doxil demonstrated a superior ther-

apeutic index (beneﬁt/risk ratio) versus current standard,

carboplatin-paclitaxel.

Surgical candidate or not

Ye s N o

Randomize Randomize

Surgery No surgery

Chemo randomization

Carboplatin +

paclitaxel

Carboplatin +

paclitaxel +

bevacizumab

Figure 1: GOG 213.

3. Small Molecules that Target

the VEGFR Receptor

Small molecule tyrosine kinase inhibitors that target the

vascular endothelial growth factor receptor are currently

being investigated in numerous clinical trials. AZD2171

(Cediranib) is a novel oral tyrosine kinase inhibitor of

VEGFR2, VEGFR1, and c-kit. Matulonis et al. [21]reported

the initial results of this agent in the management of patients

with recurrent ovarian cancer. Five patients had conﬁrmed

partial responses with an overall response rate of 18.5%.

Three patients had stable disease lasting 30, 27+, and 24

weeks. Hirte et al. [22] reported a response rate of 40.5%

in platinum sensitive patients and a response rate of 29%

in platinum resistance disease with AZD 2171 (Cediranib).

Prevalent side eﬀects included fatigue and hypertension.

Currently, ICON-6 is conducting a study of AZD2171

(Cediranib) in platinum sensitive relapsed ovarian cancer in

a three arm randomized placebo-controlled phase III trial in

combination with paclitaxel and carboplatin. (Figure 2).

Pazopanib is tyrosine kinase inhibitor of vascular

endothelial growth factor receptor (VEGFR)

−1, −2, and

−3, platelet-derived growth factor receptor (PDGFR) −α

and

−β, and c-Kit. Friedlander et al. [24]havereported

activity with pazopanib in women with advanced epithelial

ovarian cancer. Eleven of 36 subjects (31%) experienced a

cancer antigen-125 (CA-125) response to pazopanib. Overall

response rate based on modiﬁed Gynecologic Cancer Inter-

group (GCIG) criteria (incorporating CA-125, Response

Evaluation Criteria in Solid Tumors (RECIST), and clinical

assessment) was 18% in subjects with measurable disease at

baseline and was 21% in subjects without measurable disease

at baseline. Median PFS was 84 days.

Sunitinib, an inhibitor that targets the VEGFR 1, 2,

3, and platelet–derived growth factor receptors, has also

been studied in the management of patients with recurrent

ovarian cancer. Biagi et al. [25] investigated the role of

sunitinib in the management of patients with recurrent

ovarian cancer. Sunitinib was administered at 50 mg every

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