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Avastin®(Bevacizumab) for
Hormone-Refractory Prostate Cancer
Avastin Combined with Docetaxel (Taxotere)
Looks Promising as a ≥ 2nd Line Chemotherapy
Avastin Combined with Thalidomide and Taxotere
also is promising, but has
only been tested in chemotherapy-naive men.
Introduction
Avastin (bevacizumab) is a recombinant, humanized antivascular endothelial growth factor
antibody that specifically inhibits VEGF (anti-VEGF). In pre-clinical
models it has
synergistic or additive tumor inhibition effects with several chemo agents (1)
including doxorubicin,
topotecan, paclitaxel, docetaxel, and also with radiotherapy.
Changes
observed include decreased vascular vessel diameter, density and
permeability in response to Avastin treatment. These changes in the
vascular structure resulted in an increase in intratumoral uptake of
chemotherapy implying a combination treatment would be better than Avastin
alone. Also, combination treatment with radiation increased tumor
oxygenation and tumor growth inhibition.
Definitions
CR - Complete Response.
PR - Partial Response
PSA RR - PSA Response Rate (≥50 Decline in PSA).
SD - Stable Disease.
VEGF - Vascular Endothelial Growth Factor.
MAb - monoclonal antibody.
rhuMAb - recombinant humanized monoclonal antibody
How Does
Avastin (bevacizumab) work?
Curetoday has both a description and picture to help in understanding
Avastin (anti-VEGF). "Angiogenesis inhibitors work by preventing
angiogenesis, or the formation of new blood vessels in the tumor. This
strategy shuts down a tumor’s blood supply to shrink the tumor, because
tumors, like normal tissue, need nutrients and oxygen from blood to survive.
Most antiangiogenic drugs target either the vascular endothelial cell growth
factor, or VEGF—a protein secreted by certain tumors to promote the growth
of new blood vessels—or the VEGF receptor on blood vessel cells that
responds to VEGF. Avastin (bevacizumab) was the first successful drug to
attack cancer in this way (see illustration). Avastin is a MAb that attaches
to VEGF and prevents it from activating the VEGF receptor. Avastin is
approved for colorectal cancer and non-small cell lung cancer, and has shown
benefit with chemotherapy in clinical studies for a variety of other
cancers." See the
illustration also.
Studies in
Hormone-Refractory Prostate Cancer
Avastin monotherapy.
DM Reese et al
(2), studied bevacizumab monotherapy in a phase II trial. There were only 15
patients and they each received 10mg/kg rhuMAb VEGF every 14 days for 6
infusions (one cycle). Those patients who had a response or stable disease
received additional treatment. None of the 15 patients had an objective
complete or partial response after one cycle. There were no PSA responses
(≥ 50% decrease in PSA) after one cycle, but four
patients (27%) had a PSA decline of <50%, three patients (20%) had a
PSA level increase of <50%, and eight patients (53%) had a PSA increase of
>50%. The median time to objective progression was 118 days, and the median
time to PSA progression was 57 days. They concluded that a different dose
and schedule might provide better results or trials should focus on earlier
stages of the disease or used in combination with other therapies.
Avastin with Docetaxel and Emcyt,
Chemotherapy-naive, HRPC, Metastatic
J. Picus et al (3) reported on CALGB 90006 at the ASCO
annual meeting in 2003. There were 79 patients, all were
chemotherapy-naive and were metastatic. This study evaluated
taxotere 70mg/m2 IV on day 2, estramustine phosphate (Emcyt) 280 mg orally
3x/day on days 1-5 and Avastin 15 mg/kg of B on day 2,
repeated every 21 days. This was compared to CALGB 9780 which only
used taxotere and emcyt (Saverese JCO, 19:2509). In that trial, the PSA
response rate (≥ 50% decline) was 69% and the median time to progression was
11 months. Two mg warfarin was encouraged but not required and dexamethasone
8mg was given 2x/day for days 1-3.
Results (Updated from original abstract, Ning et al,
ASCO 2008).
Measurable
Disease Response Rate: 60% (32 patients had measurable disease.)
PSA Response
Rate (≥ 50% Decrease): 78%.
Median
Survival: 24 months.
Toxicity(per
2003 abstract):
No major bleeds; one patient died of mesenteric vein thrombosis; one patient
had a deep vein thrombosis; one patient had a stroke. Another patient died
from a perforated sigmoid colon thought to be unrelated to treatment (It was
later determined that this was treatment related.) One episode of febrile
neutropenia, several patients with moderate to severe fatigue, and a high
rate of uncomplicated neutropenia that rapidly resolves.
Avastin with Docetaxel,
Prior Chemotherapy Allowed, HRPC, metastatic
Di Lorenzo et
al (4) have described their phase II trial of Avastin and Taxotere in men
who had previously been treated with Taxotere and other cytotoxic drugs. In their table of patient
characteristics, they list the various chemotherapies that trial
participants had received. All had prior bisphosphonates. Prior chemotherapies
included (listed with chemotherapy, no of patients.)
-
Docetaxel,
20
-
Mitoxantrone, 20
-
Vinorelbine,
13
-
Cyclophosphamide, 5
-
Thalidomide
3,
-
Platinum
Compounds 7
No. of
Patients: 20, 20 with bone mets and 8 with bone and measurable lesions.
Dose/Schedule: Avastin, 10mg/kg and taxotere 60mg/m2 every 3 weeks. Oral
dexamethasone 8mg 12h before, immediately before and 12 h after taxotere. g-csf
was allowed if needed.
Results (No.
of Patients/ Percent):
-
Measurable
Disease: CR 0, PR 3 (37.5%), SD 2 (25%).
-
PSA ≥ 50% Decrease:
11 (55%).
-
PSA
≥ 25% to
49% Decrease: 2 (10%).
PSA SD <25% decrease to < 25% increase: 2 (10%).
Median
Overall Survival: 9 mos. (4-12.5 mos.)
Progression Free Survival: 4 mos. (2-6 mos.)
Toxicity
(grade 3 and 4 have been highlighted). Based on table 4 from (4).
|
Toxicity data experienced per
patient (n = 20) |
Tax327 Phase III (n=332) |
|
Toxicity
|
Grade 1–2 |
Grade 3 |
Grade 4 |
Grade
(any or as indicated) |
|
Neutropenia
|
8 (40%) |
3 (15%) |
1 (5%) |
32 (gr 3/4) |
|
Anemia
|
4 (20%) |
1 (5%) |
0% |
5 (gr 3/4) |
|
Thrombocytopenia
|
8 (57%) |
2 (10%) |
1 (5%) |
1 (gr 3/4) |
|
Edema
|
3 (15%) |
0% |
0% |
19 |
|
Hypertension
|
7 (35%) |
0% |
0% |
- |
|
Nausea/vomiting
|
7 (35%) |
2 (10%) |
0% |
42 |
|
Peripheral neuropathy
|
5 (25%) |
1 (5%) |
0% |
30 |
|
Lacrimation
|
5 (25%) |
0% |
0% |
10 |
|
Myalgia
|
5 (25%) |
0% |
0% |
14 |
|
Dyspnea
|
3 (15%) |
0% |
0% |
15 |
|
Fatigue |
- |
- |
- |
5 (gr 3/4); 53 overall. |
Phase III Trials With Taxotere and Avastin (CALGB 90401)
CALGB 90401: Randomized Double Blinded Placebo controlled Phase III Trial Comparing
Docetaxel + Prednisone with or without Bevacizumab in men with HRPC.
Patients could not have had prior thalidomide, bevacizumab
or any other antiagiogenesis agents. They also couldn't use concurrent
G-CSF, GM-CSF or pegfilgrastim.
Furthermore, they were not allowed to have had prior emcyt, suramin or any other cytotoxic chemotherapy (prior or
concurrent). There were two arms in this trial.
Both arms used:
Dexamethasone 8 mg po x 3 doses (changed
to may use IV)
Docetaxel 75 mg/m2 on day 1 q 21 days
Prednisone 10 mg po daily (allowed
to modify due to tox)
Arm A had the
Placebo: Placebo IV on day 1 q 21 days
Arm B had the study drug: Bevacizumab 15 mg/kg IV on day 1 q 21 days
Status: closed to new
patients. Hopefully, this trial, will lead to FDA approval for HRPC.
What Other Combinations Using Avastin Might be of Use in HRPC?
YM Ning (5) et al have studied the taxotere, avastin and thalidomide
combination. Their phase II trial is based on the hypothesis that combining
the mechanistically different anti-angiogenic agents, Thalidomide (T) and
Bevacizumab (Bv), with Taxotere would block multiple angiogenic pathways and
lead to potent anti-tumor activity. Thalidomide does not affect the target of Bevacizumab (VEGF) in
xenograft models of AIPC, but appears to alter circulating endothelial cells
and inhibits TNF expression.
Patients: All were chemotherapy naive. All had progressive metastatic castration resisitant prostate cancer (mCRPC). Total
patients enrolled: 60.
Treatment: Taxotere 75mg/m2 & Bv 15mg/kg day 1 every 21
days + 200mg thalidomide every day at bedtime and 10mg every day of
prednisone. Also they used enoxaparin for thrombosis prevention and
pegfilgrastim if grade >3 neutropenia.
Results:
PSA RR: 51 of 60 (88%); 5 had PSA declines of < 50% &
41 of 60 (71%) had a decline of > 80%.
Measurable disease: 63% overall response rate consisting of 2 complete, 18
partial, 11 stable and 1 progressive.
Progression Free Survivial: estimated median 18.2
months.
Significant toxicities: febrile neutropenia (5/60), syncope (5/60), GI
perforation or fistula (3/60), thrombosis (3/60), grade 3 bleeding (2/60).
Conclusion
Based on the
results to date, the combination of taxotere and avastin looks very
promising. By adding thalidomide to this mix, there appears to be an
even greater reason to continue this direction of treatment.
Unfortunately, for HRPC, Avastin has yet to be approved by the U.S. FDA.
Di Lorenzo et
al (4) used a reduced dose of taxotere (60mg/m2) and Avastin (10mg/kg) in
chemotherapy pre-treated men and got a PSA RR of 55% and a Measurable
disease overall RR of 62.5% (PR 3 (37.5%), SD 2 (25%)). Ning et al (5) got a
PSA RR of 88% and Measurable disease overall RR of 63% in chemo-naive
patients, but had two complete responses while Di Lorenzo had none.
The PFS numbers are very improved with the triple combination vs the double
(4 mos for double vs 18.2 for triple).
Until the
avastin, thalidomide, taxotere combination is tested on chemotherapy
pre-treated patients, it is not possible to tell whether or not adding
thalidomide makes any significant difference. We can look forward to a
trial of this option as well as the results of the phase III trial.
Author: Howard Hansen, 13 August 2008.
Note: The author is not a medical doctor and cannot render medical
advice. As a prostate cancer patient, this was written in an attempt to
understand these treatments and how it affects me. I make no claims that
this review is definitive, complete or authoritative and I request any
contributions to, or clarification of the subject which might contribute to
the issue or inquiry. In conjunction with a medical team, every cancer
patient must make their own decisions regarding treatment options. Your own
medical team's directions should be carefully followed.
(1)
Gerber HP, Ferrara N,
Pharmacology and pharmacodynamics of bevacizumab as monotherapy or in
combination with cytotoxic therapy in preclinical studies,
Cancer Res. 2005 Feb 1;65(3):671-80.
(2) David M. Reese, PhD,Paige Fratesi, BS,
Michelle Corry, RN, William Novotny, MD,
Eric Holmgren, PhD,and Eric J. Small, MD, A Phase II Trial of Humanized Anti-Vascular Endothelial Growth
Factor Antibody for the Treatment of Androgen-Independent Prostate Cancer, The Prostate Journal Volume
3 Issue 2 Page 65 - April/May/June 2001
doi:10.1046/j.1525-1411.2001.32007.x
(3) J. Picus, S. Halabi, B. Rini, N. Vogelzang, Y. Whang, E.
Kaplan, W. Kelly, E. Small; The use of bevacizumab (B) with docetaxel (D)
and estramustine (E) in hormone refractory prostate cancer (HRPC): Initial
results of CALGB 90006; ASCO 2003, Abstract No: 1578.
(4) Di Lorenzo G, Figg WD, Fossa SD, Mirone V, Autorino R, Longo N, Imbimbo C,
Perdonà S, Giordano A, Giuliano M, Labianca R, De Placido S, Combination of
Bevacizumab and Docetaxel in Docetaxel-Pretreated Hormone-Refractory
Prostate Cancer: A Phase 2 Study, Eur Urol. 2008 Feb 5. [Epub ahead of
print] Eur Urol (2008), doi:10.1016/j.eururo.2008.01.082. (5) Y. M. Ning, P. M. Arlen, J. L. Gulley, W. D. Stein, A. T. Fojo, L.
Latham, J. J. Wright, H. Parnes, W. D. Figg, W. L. Dahut, Phase II trial of
thalidomide (T), bevacizumab (Bv), and docetaxel (Doc) in patients (pts)
with metastatic castration-refractory prostate cancer (mCRPC), J Clin Oncol
26: 2008 (May 20 suppl; abstr 5000)
Access to Avastin. Avastin is very expensive. Many insurance plans do
not cover it. Here's what one member of the email list researched about
this:"I've done some research and found that
Genentech (maker of Avastin) has an Access Solutions department that works
with patients (and doctors) and insurance companies to see what will be
covered. If they cannot work out a solution with the insurance company,
they will work with the patient to have Genentech reimburse for the Avastin.
I called and spoke with a delightful woman who assured me that they will
help with securing the drug. The Access Solutions number for patients is 1
(888)249-4918 and a real person answers! If any of you are thinking of
Avastin as a possibility, please call that number or go to
https://www.genentechaccesssolutions.com/index_avastin.jsp ."
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