Thema: Presse: Avastin and CPT-11 in the treatment of malignant glioma
Presse: Avastin and CPT-11 in the treatment of malignant glioma
Katja[a]
01.10.2005 19:44:12
Avastin and CPT-11 in the Treatment of Malignant Glioma
Dr. Virginia Stark-Vance, MD
Most patients with malignant glioma begin treatment with surgery, radiation therapy, and chemotherapy. Since TMZ received FDA approval in 1999, many patients with anaplastic astrocytoma and other high grade brain tumors have been offered treatment with TMZ.
However, there are patients who cannot tolerate TMZ or who have tumors that appear to be resistant to TMZ. The search for a well-tolerated and effective drug or combination of drugs is expected to continue, until the real "cure" has been identified.
Most patients still relapse after, or even during, treatment with TMZ. 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 (Camptosar) 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 Avastin (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 Carboplatin, BCNU, CCNU und TMZ. It may be that Avastin, added to TMZ after radiation therapy, may be better than TMZ 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.
Copyright © 2004 dfw-neuronetwork
Saturday June 18, 2005
Dr. Virginia Stark-Vance, MD
Most patients with malignant glioma begin treatment with surgery, radiation therapy, and chemotherapy. Since TMZ received FDA approval in 1999, many patients with anaplastic astrocytoma and other high grade brain tumors have been offered treatment with TMZ.
However, there are patients who cannot tolerate TMZ or who have tumors that appear to be resistant to TMZ. The search for a well-tolerated and effective drug or combination of drugs is expected to continue, until the real "cure" has been identified.
Most patients still relapse after, or even during, treatment with TMZ. 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 (Camptosar) 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 Avastin (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 Carboplatin, BCNU, CCNU und TMZ. It may be that Avastin, added to TMZ after radiation therapy, may be better than TMZ 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.
Copyright © 2004 dfw-neuronetwork
Saturday June 18, 2005
Katja[a]
