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However, there are
patients who cannot tolerate Temodar or who have tumors that
appear to be resistant to Temodar. The search for a
well-tolerated and effective drug or combination of drugs is
expected to continue, until the real “cure” has been identified.
While there are
patients – up to 25% - who seem to derive long term benefit from
early treatment with Temodar – most patients still relapse
after, or even during, treatment with Temodar. For those
patients, there is a desperate need for an effective
alternative. This is the story of how one glioblastoma
survivor directed her own therapy and set in motion a trial of
two controversial drugs.
Dorothy was diagnosed
in 2001 with a left temporal glioblastoma. For one year
after radiation therapy, she received chemotherapy with Temodar.
Although the original tumor location remained stable, one of her
follow up MRI scans showed a 1 cm tumor in the left occipital
lobe. For the next several months, Dorothy received
treatment with stereotactic radiation and several chemotherapy
drugs. By March 2004, her extensive tumor recurrence
affected her vision and her right motor function. Although
her treatment with CPT-11 (CamptosarÒ) seemed to keep the tumor
stable, she and her husband continued to investigate other
options. She knew that, because of her previous therapies,
most clinical trials would be closed to her.
Dorothy’s husband
read about AvastinÒ (bevacizumab) on the internet shortly after
its approval by the FDA for the treatment of colon cancer.
He knew that Avastin was an antibody against human vascular
endothelial growth factor (VEGF) and he also knew that many
glioblastomas “overexpress” VEGF. It is certainly to his
credit that he immediately considered that Avastin might be an
effective therapy for his wife’s glioblastoma!
When Dorothy and her
husband mentioned that they wanted to add Avastin to her
treatment regimen, I was concerned that the drug may not be safe
in brain tumor patients. Genentech, the pharmaceutical
company which developed Avastin, specifically excluded patients
with brain tumors in the early clinical trials. One patient with
an unsuspected brain metastasis had suffered an intracranial
hemorrhage. Dorothy, undeterred, said that she was willing
to take that risk.
My other concern was
that Dorothy’s insurance company would not pay for the cost of
the drug (expected to be about $3000 per dose). To my
surprise, Dorothy’s insurance company provided the drug for her
therapy. Even so, she was hospitalized for her first
treatment, to keep her under close observation for the first 24
hours.
Dorothy received
Avastin every two weeks, together with her CPT-11 treatments.
She noticed an improvement in her right-sided strength
immediately. After only one month of therapy, her MRI
showed a dramatic improvement.
Within a few days,
another glioblastoma patient returned to clinic with her new
MRI. Not only was her tumor much more extensive, she had
already discussed with her neurosurgeon and her radiation
oncologist further intervention – and had been turned away.
Nancy was determined to see her son graduate from the Naval
Academy. In early April, this didn’t seem possible.
Nancy, like Dorothy,
had received extensive chemotherapy in the past. Although
she had never received CPT-11, she was willing to try it.
I told her that “we might consider” adding Avastin to her
treatment, because another patient had seemed to improve with
the combination. She read everything she could about the
two drugs and agreed on a trial of one month of therapy:
four weeks of CPT-11, with Avastin every other week. Thus,
the “protocol” included:
Decadron 10 mg IV
every week
Zofran or other
anti-nausea drug IV every week
Avastin 5 mg/kg IV,
every two weeks
CPT-11 125 mg/m2 IV,
every week
After the first four
weeks, the patient had a one or two week break and a follow up
MRI.
Nancy also
experienced a dramatic improvement. A few days
later, I brought her scan to a conference to show Dr. Henry
Friedman, who had begun clinical trials with CPT-11. Dr.
Friedman later asked Genentech to sponsor further clinical
trials with Avastin at the Brain Tumor Center at Duke.
Because of the large number of brain tumor patients seen at
Duke, this would provide a way to study Avastin with CPT-11 (or
any other drugs) very rapidly.
After the initial
results with Dorothy and Nancy, I decided that other patients
should have the opportunity to receive this combination.
Of course, there was still a concern that there would be other
side effects, possibly even cerebral hemorrhage. CPT-11 is
far from a perfect drug. Patients can develop profuse, watery
diarrhea, severe nausea and vomiting, and low blood counts.
Although I tried to standardize all patients to begin CPT-11 at
125 mg/m2 per week, some could not tolerate this dose.
Some had to cut back the CPT-11 to every other week. Two
patients had clear improvement on their MRI scans but had to be
hospitalized for diarrhea. Fortunately, I found that they
responded to another combination:
Avastin 5 mg/kg every
other week
Carboplatin, AUC 2
CPT-11 60mg/m2
One patient who was
responding to CPT-11 and Avastin did develop a cerebral
hemorrhage. This gentleman was a retired scientist who
passionately pursued every new therapy. He had required
therapy with a blood thinner because of his history of blood
clots and of course there is the concern that this may have
increased the risk of severe hemorrhage. Fortunately, no
other patients have developed this complication.
In the colon cancer
studies with Avastin, a very small percentage of patients
developed gastrointestinal perforation. One of my
glioblastoma patients also developed a colon perforation and
required emergency surgery. She had had previous
evaluation by a gastroenterologist but had refused colonoscopy,
so it is unclear whether a problem could have been detected
earlier. At any rate, she survived the surgery and had a
good response to treatment with Avastin and CPT-11.
More than one year
later, I have treated over thirty patients with this
combination. Only three have had tumor growth during the
first month of treatment with Avastin and CPT-11. Others
have had a good response to treatment with almost total
resolution of the tumor, only to have new tumor appear on a
subsequent MRI. Fortunately, some of these patients have
responded to further treatment.
I have used Avastin
in a few patients in combination with Temodar, Carboplatin,
BCNU, and CCNU. It may be that Avastin, added to Temodar
after radiation therapy, may be better than Temodar alone.
It is clear that Avastin can interfere with wound healing, and
therefore it could not be used immediately after surgery.
The obvious question
is how to improve on what seems to be a very effective – but
still toxic – therapy. It would be important to identify
which patients may be at risk for cerebral hemorrhage or
gastrointestinal perforation with Avastin. It would also
be preferable to use other drugs with less toxicity than CPT-11
or at least develop other ways to treat its toxicities.
Currently my patients receive an instruction sheet for dealing
with diarrhea, and this seems to be helpful to those beginning
CPT-11 for the first time.
Recently, I
summarized the results of the first patients treated with
Avastin and CPT-11 and presented them at the World Federation of
Neuro-oncology in Edinburgh. Even though the regimen is far from
perfect, it seems to work well in the majority of patients with
relapsed malignant glioma. However, I would still
encourage all patients to try Temodar and the less toxic
regimens first.
Also, I would warn
patients to check carefully to see whether Avastin and CPT-11
are covered under their insurance plan. While most of my
patients have been able to receive Avastin and CPT-11 under
their private insurance plans, Medicare and Medicaid patients
aren’t so fortunate. However, there are programs available
from the pharmaceutical companies to help with the cost of the
drugs. I understand that Genentech is providing Avastin
for the Duke clinical trial, and would certainly encourage
anyone who could to enroll in that trial. |
