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Our doctors are happy to discuss your individual case with you. Serious inquiries only, please. To request an initial
team consultation, call Dr. Arenson, For more information
about CNI's Brain & Spinal Tumor Team, |
The CNI Center for Brain & Spinal Tumors Team in our strategy for cure employ neurosurgery, combined chemotherapy and radiation therapy, sometimes followed by another surgery or stereotactic radiosurgery, and biological therapy. Using this approach we have had very encouraging results over the last 5 years.
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Surgery
has been, and remains, the treatment modality with the greatest effect
on outcome for all high grade brain tumor patients. While patients with
low-grade tumors can be cured occasionally by surgical removal, high-grade
tumors are not surgically curable. Studies clearly demonstrate that the
removal of more than 90% of a high grade tumor is associated with substantial
improvement in survival and, when combined with aggressive and effective
post-surgical therapy, can result in cure for some patients including
those with glioblastoma multiforme.
Therefore, the goal of the CNI Center for Brain & Spinal Tumors neurosurgeons is to remove as much tumor as possible without causing unacceptable neurological deficits. This is a challenging goal which requires experience and expertise as well as sophisticated technical support. In this section we will provide you with details of our approach and our results.
New Technology greatly benefits neurosurgeons in determining before surgery the full extent of the tumor (MRI spectroscopy), and the risks of producing unacceptable neurological deficits (functional MRI
Some patients have tumors that develop in areas of the brain that are important regions for the control of speech, language, and other neuropsychological function. In order to preserve as much function as possible when removing brain tumors, doctors may decide to do part of the operation while the patient is awake. If an awake procedure is elected, one or more neurosurgeons, an anesthesiologist, a neuropsychologist, a neurologist and, several operating room technicians will take part in the patient's care.
There is minimal discomfort because the potentially painful part of the operation is done while the patient is asleep and under general anesthesia. During the procedure, most people spend between 30 minutes and 2 hours for the awake part of the operation. After the patient becomes alert, the neuropsychologist begins testing speech, language, memory, or other neuropsychological tasks the person will have practiced earlier that day in the hospital or at the doctor's office. The specific tasks used during an operation will depend upon the nature and location of the lesion and what functional areas of the brain are likely to be involved in an individual's surgery.
Many people do not recall anything about having been awake during the operation, though some recall parts of the process. If your doctor feels that awake craniotomy is a necessary step you will be fully informed of what to expect in you specific situation.
To preserve as much neurological function as possible while optimizing tumor removal, techniques are used which map areas of the brain that contain important functions, especially language and sensory-motor functions. One such technique is called functional MRI in which MRI scanning is used to map functional areas of the brain using special software. Another technique, pre-operative functional mapping, requires an operation to place a grid of electrodes on the surface of the brain followed by a period of evaluation of brain function outside the operating room by a specially qualified neurologist. The brain is directly stimulated and the responses are recorded so that the surgeon will have an actual map of the functions of the area around the tumor. This information will be used to plan the best surgical approach.
Finally, intraoperative functional mapping, is frequently use as well. Specific areas of the brain can be electrically stimulated during the course of an operation to determine where the functional areas lie and to allow the surgeon to use the information to try to minimize any clinical deficits. This is usually done while the patient is under general anesthesia and unconscious, but occasionally this requires that the patient be awakened for language testing. A CNI neurologist and, if necessary, a neuropsychologist assists the neurosurgeon in this specialized technique.
The mapping techniques involve cooperation between the CNI Center for Brain and Spinal Tumors, the neurologists, and the staff of the CNI Epilepsy Center. This is an example of the advantage patients have at CNI, where complementary programs exist.
This is a relatively new technique, not universally available to neurosurgeons, which is used routinely at CNI. Using modern imaging technology, a system is created whereby the neurosurgeon, during surgery, can place a probe anywhere in the brain, and see, three dimensionally, where the probe is in the brain by looking at a screen that shows a scan of the brain and the tumor. This enables the neurosurgeon to continue removing tumor in situations where, without frameless stereotaxy, surgery would have to be discontinued.
As a result of this valuable technology, our patients have a high percentage of complete, or near complete, removal of their tumors which gives them a better chance for survival. In the near future (See the Neuroradiology Section) we hope to improve upon this technology by mapping areas of the brain which contain tumor which cannot be identified on standard imaging such as MRI scans, but instead by biochemical analysis of the brain. This will sometimes enable neurosurgeons to remove more tumor than in currently possible.
A laser beam is a form of light energy powerful enough to be used as an instrument which can cut tissues more precisely in some situations than other techniques. CNI neurosurgeons routinely us lasers to operate on their patents in situations where they must come dangerously close to important structures. They do this with the additional benefit of an operative microscope.
Three-dimensional radiation therapy planning, stereotactic techniques, and intensity modulated radiation therapy (IMRT) are some of the techniques currently available at CNI that are helping us achieve the goal of increasing the efficacy while minimizing the risks of radiation therapy.
Radiation therapy has been available for the treatment of central nervous system tumors for many years, but recently, the level of sophistication utilized by radiation oncologists has grown markedly. Radiation in relatively high doses is a proven effective treatment for central nervous system tumors which significantly prolongs survival. Radiation can also affect normal brain; therefore, there is a limit to how much can be given. Recently the emphasis has been on development of techniques to allow more aggressive treatment of tumors while minimizing the exposure of normal brain to radiation. Successful achievement of this goal will increase survival while reducing both short and long term effects of the treatment.
While radiation therapy is effective it is seldom curative. Therefore much attention is being paid at the present time to find ways to make radiation therapy more effective such as agents that sensitize tumors to the effect of radiation therapy. At CNI, our current approach is to administer chemotherapy and radiation therapy simultaneously in order to take advantage of the possible radiosensitizing effects of the chemotherapeutic agents and to make sure neither important modality is delayed.
Finally, focal hyperintense radiation therapy, commonly referred to as gamma knife or stereotactic radiosurgery, is receiving much attention and is currently available to patients in the CNI Center for Brain & Spinal Tumors. These techniques, which differ somewhat in their applicability, are ways to focus radiation intensely on a small area of residual disease in order to destroy the tumor tissue while minimizing exposure to the normal tissue nearby. This treatment is usually given in one daily treatment and has been used in our Center in situations where tumor cannot be eliminated by surgery or by chemo-radiation therapy. This technique is somewhat limited by the size and shape of the tumor, but it is frequently used in our Center with significant benefit to our patients. These techniques are also very effective treatment for low grade tumors in locations where they cannot be safely removed surgically or tumors that have spread to the brain from other parts of the body.
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Currently, the CNI Center for Brain & Spinal Tumors employs an aggressive approach to post surgical care of patients with primary high-grade gliomas. Aggressive treatment is appropriate since the greatest threat to the quality of life and survival is posed by the tumor itself, not the treatment. Our aggressive approach emphasizes use of combination chemotherapy plus biological therapy, both during and following standard radiation therapy.
The rationale for using combination chemotherapy rather than a single agent chemotherapy (the current community standard is single agent temozolomide) is simple: there is no precedent for the predictable curability of human cancer with any single chemotherapy drug, no matter how effective the drug might be. This dictum was recently reiterated by DeVita in his authoritative textbook entitled “Cancer, Principles and Practice of Oncology”. We also believe that the results achieved with single agent Temodar, published recently by Stupe, et al., can be improved upon by adding other drugs to the Temodar. We have published our results in the journal “Neuro-oncology” in the summer of 2005 and presented them in Scotland at the Annual Meeting of the World Federation of Neuro-oncology. The abstract that we published is shown here:
Encouraging results for a novel chemotherapeutic regimen in newly diagnosed glioblastoma multiforme
Arenson, E., Bank, J., Pierick, M., Greenwald, C., Fullagar, T., and McVicker, J. from the Colorado Neurological Institute and Swedish Medical Center, Englewood, CO, USA.
Substantial benefit from chemotherapy of cancer requires effective combinations; nevertheless, monotherapy with temozolomide (TMZ) has emerged as the “standard” treatment of glioblastoma multiforme (GBM). We report results of treatment of GBM with the novel combination of BCNU, irinotecan (CPT11) and TMZ (BITE). Four patients were excluded from this treatment because of: expected survival < 3 months, absence of caregiver or 24 hour care requirement. Thirty-seven patients with newly diagnosed GBM were treated between August, 1999 and October, 2002. Mean age was 53.4 years. Thirteen patients had bilateral and/or multifocal disease. Nine had gross total resection, 27 subtotal resection and 1 biopsy, as determined by early post-operative contrast MRI. Treatment consisted of three courses of CPT11 (400 mg/m2 x 1) and TMZ (200 mg/m2 x 5) given every 21 days during standard radiotherapy (RT) (phase I) to which BCNU (40 mg/m2 x 3) was added after RT for up to 6 monthly courses as tolerated (phase II). Three patients did not complete phase I because of patient choice, neurological decline or death from intratumoral hemorrhage unrelated to treatment. Two additional patients did not proceed to phase II because of poor performance status. Thirty-two patients received 115 courses of BITE (mean 3.4) and had episodes of grade III/IV toxicities as follows: GI 12%, neutropenia 42% and thrombocytopenia 11%. There were 2 deaths during phase II unrelated to disease progression: one disseminated CMV and one bacterial pneumonia. One patient survived an atypical mycobacterial pneumonitis, and one survived an episode of BCNU pneumonitis. With minimum follow-up of 30 months, mean survival is 19 months. Overall survival is 59% 1-year, 30% 2-year, 19% 3-year, and relapse-free survival is 46% 1-year, 22% 2-year and 11% 3-year. Six patients are alive (16%), five without evidence of disease and one with stable disease from 37 to 48 months post diagnosis. For patients with initial gross total resection (24%), relapse-free survival was 67% 1-year, 33% 2-year and 11% 3-year. We conclude that: 1. BITE is toxic, but effective 2. polychemotherapy should not be abandoned in GBM 3. BITE deserves further study with efforts to reduce toxicity 4. patients with gross total resection may survive long-term with aggressive post-surgical treatment.
In this study we utilized a combination of temozolomide and irinotecan during radiation therapy, and then added BCNU after radiation therapy for up to six monthly cycles. This therapy produced 2, 3 and 4 year survival rates for GBM, superior to that which can be expected from temozolomide alone. However, this regimen was quite toxic and has been modified subsequently to reduce toxicity and, hopefully, preserve its effectiveness. Currently we use temozolomide and irinotecan during radiation therapy. The temozolomide is given daily in low doses and the irinotecan is given IV weekly for up to six doses. This has been well tolerated. Using this treatment, it is extremely unusual for tumors to grow during this first phase of therapy which is not an infrequent occurrence in less aggressive approaches.
Following radiation therapy, patients receive alternating monthly courses of temozolomide and BCNU or temozolomide plus irinotecan plus Taxol. Biological therapy, usually thalidomide, is added as soon as tolerability of the chemotherapy regimen has been established.
This regimen has been well tolerated. Modifications are made in order to insure tolerability and good quality of life. MRI scans are done every eight weeks to insure good tumor response. If tumor control is not achieved, the regimen is modified by substituting other drugs such as carboplatin, VP16, or Navelbine and other biologicals such as high dose tamoxifen, Accutane or Tarceva. We continue to observe an encouraging number of long term survivors (greater than 3 years) with this approach and have had a significant reduction in serious side effects and complications.
In 2004, the CNI Center for Brain & Spinal Tumors established an annual celebration event for patients surviving at least three years from high-grade primary central nervous system tumors. The first year we invited 25 patients, and in 2005 ear we invited 50. In 2006 we expect this number to continue to grow. These patients, most of whom are enjoying life with good function, are a testament to the potential benefit of the aggressive approach that we take.
Obviously, not everybody can or should be treated with this type of treatment. We are careful to select patients who are motivated, healthy enough to tolerate the aggressive therapy and have good care support at home. Other patients may receive less aggressive treatments.
In summary, the CNI Center for Brain & Spinal Tumors takes a unique and aggressive approach to the treatment of selected patients with primary central nervous system tumors with the intent to cure the disease. We have a significant and predictable number of survivors beyond three years. In fact, no patient in our Program who has survived more than 36 months without progression of their disease has relapsed. Many of the survivors are beyond 5 years at this time. We believe that this is the right approach and will continue to pursue it. Obviously, we do not have a final answer for every patient and regret that we cannot do better. We can say, however, that we will continue to try and that, as new treatments become available, they will be incorporated appropriately into our plan.
A minority of adult patients with primary brain tumors have low-grade tumors. These tumors include grade II astrocytoma, grade II oligodendroglioma, and a mixture of both. For low-grade tumors where there is no evidence of early evolution to high-grade, surgery can be curative. Unfortunately, despite the advances in surgery that allow a higher number of surgical cures and a greater likelihood of successful surgery (greater than 90% removal), most patients with low-grade tumors are left with residual disease following their surgery. Perhaps this is because these tumors present more insidiously over longer periods of time before the symptoms lead to the diagnosis and, therefore, the tumors are larger once discovered. This problem (that is, a significant majority who has residual disease after their surgery) has become more apparent with recent advances in imaging, especially MRI spectroscopy. Treatment of these patients is controversial. It has not been established in the medical literature that radiation is indicated for patients prior to disease progression although there is evidence that these tumors respond to radiation. The role of chemotherapy is even less established despite recent reports that demonstrate that chemotherapy regimens such as PVC (procarbazine, CCNU, and vincristine) can produce responses in low-grade tumors, especially oligodendrogliomas.
We have decided to offer chemotherapy to all patients with incompletely removed low-grade tumors in order to reduce the incidence of relapse and evolution to more aggressive (high-grade) tumors. We have used a modification of PVC in which procarbazine has been replaced by the more tolerable and efficacious drug, Temodar, and the drug carboplatin has been added in order to reduce exposure to CCNU which has substantial cumulative toxicities. Over the last 5 years, we have used this approach to treat 48 patients. Thus far, only six have relapsed. Our results, as shown in the abstract below, have been submitted to the American Society of Clinical Oncology for the annual spring meeting:
Use of modified PCV chemotherapy as principal therapy for adults with
incompletely resected or recurrent low-grade glioma: A retrospective review
EB Arenson, J Bank, M Pierick, C Greenwald, J McVicker, JP Elliott, JD Day, TM Fullagar; The Colorado Neurological Institute, Englewood, Colorado
Background: In order to assess outcomes of patients treated with chemotherapy versus a more standard approach of radiotherapy (RT), we reviewed 48 patients with newly diagnosed, partially resected or recurrent low-grade glioma (LGG) treated between 1996 and the present.
Methods: Patients were divisible into three groups: those treated with chemotherapy + RT before (Group A, 28 patients) or after (Group B, 13 patients) radiographic progression, and those with recurrences after treatment with RT (Group C, 7 patients). Diagnoses included astrocytoma (23%), oligodendroglioma (48%) and mixed glioma (29%). 39 patients were treated with chemotherapy alone and 9 received post-chemotherapy RT. Chemotherapy consisted of PCV in one case; all other patients received modified PCV (MPCV), which variably included addition of carboplatin (200-360 mg/m2) and etoposide (150 mg/m2) and substitution of temozolomide (150 mg/m2/day x 5 doses) for procarbazine. The intent was to treat monthly for one year.
Results: Patients received a mean of 10 courses of MPCV; 481 cycles were given. There were no deaths or admissions during chemotherapy. Grade III/IV toxicities occurred in 108 cycles (25 patients), 107 hematologic and 1 GI. Late effects included 1 case of MDS and 1 AML. There were no cases of disease progression during chemotherapy. Two patients stopped MPCV early, one because of worsening seizures (2 cycles) and one by personal preference (1 cycle); both died of disease. With a median follow-up of 46 months (range 4-120) from initiation of chemotherapy, overall survival and progression-free survival were 89% and 79% for Group A, 91% and 83% for Group B, and 100% and 86% for Group C. Of 6 patients (12.5%) who recurred after completing chemotherapy, 2 have died; both had received post-chemotherapy RT and had clinical features of GBM. Four patients are either lost to follow-up (2) or alive with stable disease (2) following additional treatment.
Conclusions: 1. MPCV is a tolerable regimen which can be given more aggressively than standard PCV. 2. There is minimal risk of early disease progression with MPCV. 3. Results support a prospective trial comparing MPCV to RT in patients with progressive unresectable LGG, and use of MPCV as salvage therapy for patients who fail RT.
Our experience suggests that radiation therapy can be delayed or eliminated in most patients by the use of chemotherapy. This is our current recommendation.
Following completion of this aggressive phase of chemotherapy, patients then go on to a final biological therapy phase in which they will take the drug tamoxifen in high doses plus or minus the drug thalidomide. These drugs are not chemotherapeutic agents, and as such, are not nearly as toxic. They are, however, agents which have been shown to have a beneficial effect on malignant brain tumors in such a way that the tumor will either stop growing or become more differentiated and therefore less likely to progress. We have had very encouraging results with this phase of therapy which has been well tolerated by our patients.
Psychological services available in the CNI Center for Brain & Spinal Tumors include assessment and treatment from the relevant psychological disciplines: Clinical Neuropsychology and Health Psychologists (PhD or PsyD) have postdoctoral specialty training in the medical and neurologic aspects of behavior and human function.
Neuropsychological evaluations provide detailed, non-invasive assessment of a host of brain functions: memory, attention, mental organization, problem-solving, speech/language, and visual-perceptual areas are typically assessed. It is often desirable to assess functional brain changes caused by tumor processes pre-operatively, in order better to plan the neurosurgery and to anticipate possible or likely post-operative changes. Similarly, neuropsychological assessments of cognition in the post-operative period can help guide rehabilitation and measure its progress, and can be instrumental in assisting patients with return to work or lifestyle planning after returning home. If neurobehavioral symptoms like impulsivity or anxiety emerge or worsen at any time, neuropsychologists can evaluate the complex potential causes of such symptoms and offer clinical interventions to treat the problem. Neuropsychologists can help patients and families cope with changes brought on by the brain tumor.
Sometimes, too, neuropsychology plays an important role in the operating room, helping guide neurosurgeons to minimize changes in speech, language and other aspects of cognitive function during awake craniotomies.
Finally, clinical health psychology is the discipline involved in the evaluation and treatment of problems in coping and adjustment, and in dealing with emotional and interpersonal changes in such areas as mood, anxiety, relationships, sexuality, and so on. Psychotherapy, counseling, and behavioral medicine techniques like clinical hypnosis, are among the approaches health psychologists bring to patients struggling in such domains.
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Colorado Neurological
Institute Center for Brain & Spinal Tumors
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