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Philosophy of Treatment

Dr. Arenson has had the good fortune to witness the triumph over childhood leukemia and many other cancers of adults and childen through the creative use of combination chemotherapy. When he made his decision in 1995 to commit himself to the treatment of  adults with primary and metastatic brain tumors, including glioblastoma multiforme (GBM) and anaplastic glioma, he did so with the goal of cure. He believes strongly that the only way to achieve this goal is to treat with this intent. Curability of cancer remains achievable only through the use of combinations of effective chemotherapy drugs. To this date, there is no malignancy which can be cured by single agents or, unfortunately, new and sophisticated targeted biotherapy. This conviction is echoed by Dr. Vincent DeVita who authors the authoritative textbook, Medical Oncology, now in its eighth edition. This not to say that newer agents, such as bevacizumab (Avastin) for example, should not be used or do not play an important role. The crucial point is that, if cure is the goal, we must use the tested and proven approach until something better comes along. 

Dr. Arenson has also spearheaded the development of a comprehensive program for malignant melanoma at Swedish Medical Center which will include all effective therapies, a multi-disciplinary team, clinical trials, and an immunotherapy treatment center (ITC). The goal will be the same; to strive for cure.    

Proven Results


The information shown in this section is a summary of our recent analysis of patient outcomes treated by Dr. Arenson and his staff at the Colorado Neurological Institute. The patients with glioblastoma multiforme (GBM) were treated between 2003 and 2010, while the patients with low grade (grade II) glioma were treated between 1995 and the present. Both groups were uniquely treated with combination chemotherapy instead of standard single drug treatment with temozolomide. This is based on Dr. Arenson’s awareness that, with very rare exceptions, no cancer can be treated successfully with a single drug. The results for both groups of patients, despite relatively small numbers compared to large university programs, are superior to standard treatment and have been presented at prestigious meetings, but not yet published except in abstract form. We believe that these exceptional outcomes are a result of both the choice of treatment that comes from four decades of experience combined with Dr. Arenson’s personalized and flexible approach.

GLIOBLASTOMA

LOW GRADE GLIOMA

Treatment of Glioblastoma with Modified BITE 2003-2010

Patients were treated with a combination of drugs called modified BITE (mBITE) which includes BCNU, irinotecan, temozolomide and paclitaxel. All four drugs may be used in combination but are never given at the same time

    The use of multi-agent chemotherapy to treat glioblastoma (GBM) is based on the fact that single agent therapy seldom, if ever, cures cancer. We report a retrospective review of 74 patients treated by investigator choice between July, 2003 and January 2010 using a modified multi-drug chemotherapy regimen. All treatment was conducted by the Colorado Neurological Institute (CNI).










    The “Stupp” data refers to data from Dr. Roger Stupp of Switzerland who was the principle investigator of the studies which demonstrated the superiority of radiation plus temozolomide (TMZ) to radiation alone.

A subgroup of patients termed “Good Risk” presents a striking deviation from the overall survival curve. “Good Risk” patients were defined as being under the age of 60, with at least 90% of the tumor surgically removed, and with a post-treatment performance level good enough that they could care for themselves.
















    The arrow on the graph above corresponds to the point in treatment (approximately 18 months from diagnosis) after which there is a dramatic improvement in survival, as shown by the flatter curve with fewer events.

We conclude that multi-agent chemotherapy is tolerable and superior in efficacy to single agent TMZ in a single institution. It appears that about half the patients derive the most benefit and may be identifiable at diagnosis using gene expression analysis, (L. Liau, personal communication).

Notes: presented in Nov 2010 in Montreal, Canada at annual meeting of Society for Neuro-oncology; June 2012 Maui, Hawaii Rocky Mountain Neurological Society.


Superior Survival in Glioblastoma with Multi-agent Chemotherapy


Introduction

    The use of multi-agent chemotherapy to treat glioblastoma (GBM) is based on the fact that single agent therapy seldom, if ever, cures cancer. We report a retrospective review of 74 patients treated by investigator choice between July, 2003 and January 2010 using a modified multi-drug chemotherapy regimen.


Methods

    In a previous report (J.Neuro.Oncol.,May 2005,) we presented encouraging results of 37 patients with newly diagnosed GBM treated with BCNU, irinotecan and temozolomide (BITE). Subsequently, we modified BITE to reduce toxicity (mBITE). Patients received daily temozolomide (TMZ) and weekly CPT-11 during radiotherapy (RT) and monthly cycles of TMZ, CPT-11 and paclitaxel alternating with TMZ and BCNU after RT. Patients were treated consecutively save 8 who either elected standard TMZ alone or no post-surgical treatment.


Results

    Patients were treated for variable periods of time depending on response and tolerance. All patients experienced at least one episode of grade III/IV hematologic toxicity and 24 patients had grade III/IV G.I. toxicity. There were 16 serious infections and 1 death unrelated to GBM (pneumonia). With a median follow-up of 39 months, median survival was 19 months. By Kaplan-Meier analysis, survival is predicted to be 83% 1 year, 48% 2 year, 37% 3 year, 28% 4 year, and 19% 5 year. A subgroup (24%) of good risk patients defined by high grade resection, age >60 and KPS <70 had median survival of 36 months and 55% predicted 5 year survival. By Chi square analysis, these results are superior to those reported for TMZ alone by Stupp et al, (The Lancet Oncology, May 2009). There is a conspicuous shift in the survival curve at 20 months which seems to predict superior outcome for those patients (approximately 50%) who reach this point without relapse.


Conclusions

    We conclude that multi-agent chemotherapy is tolerable and superior in efficacy to single agent TMZ in a single institution. It appears that about half the patients derive the most benefit and may be identifiable at diagnosis using gene expression analysis, (L. Liau, personal communication).

Treatment of Low-Grade Glioma with Modified PCV Chemotherapy 1995-2012

Between 1995 and January, 2012, we treated 64 patients with low grade (grade II) gliomas (LGG). The median follow-up is 79 months and the mean is 75 months, range 14-196. There were 17 astrocytomas, 32 oligodendrogliomas (ODG) and 15 mixed tumors. Of 37 patients whose tumors were tested for the 1p19q gene deletions, 23 were positive. All of those tested had at least a component of ODG. 9 additional patients with ODG were not tested. Of these 64 patients, 52 were treated with chemotherapy and 12 have received no post-surgical treatment. To the best of our knowledge, a group this large treated with primary chemotherapy for LGG is unique. The choice of chemotherapy was based on the initial reports of Cairncross et al that oligodendroglioma, both grades II and III, was responsive to a chemotherapy regimen consisting of procarbazine, CCNU, and vincristine (PCV). This regimen is quite toxic, and most patients cannot tolerate more than six months of treatment which, based on the pediatric experience, is not ideal.  Subsequently, temozolomide was shown to be active in all grades of gliomas and became the predominant choice for low grade tumors despite the fact that cancer is virtually never curable with single agent chemotherapy. Thus we chose, eventually, to combine temozolomide with PCV by removing the most toxic drug, procarbazine, and alternating carboplatinum, an active drug in LGG, with CCNU (mPCV) in order to reduce bone marrow toxicity. Herein we present retrospectively our experience with this group of patients.













    Twelve patients have been followed since surgery without progression. The remaining 52 patients were treated with chemotherapy because of progression on serial imaging or because the location and volume of tumor was deemed an immediate threat. This regimen was well tolerated; there were no treatment related deaths and 1 hospitalization for shingles. The mean number of monthly courses of mPCV was 12 with a range of 1-20. Of 632 monthly courses, there were 73 episodes (12%) of grade III/IV leukopenia and 40 episodes (6%) of grade III/IV thrombocytopenia. Of 52 patients treated, 16 have relapsed. One progressed during chemotherapy and died of GBM at 31 months. The next earliest death occurred at 49 months and the latest at 132 months. All whose tumors recurred as glioblastomas (9) died. The other seven have responded to salvage therapy. Overall survival is 84% and relapse-free survival is 70%.













    Analysis of survival as a function of tumor type indicates that no deaths occurred among 22 patients who tested positive for 1p19q deletion. Of the 20% of patients whose tumors shrank significantly after treatment with mPCV, there have been no relapses or deaths so far regardless of the type of tumor or genetic status. Since our follow-up is too short to determine median survival, we cannot yet assess long term benefit of this treatment. However, we can conclude that primary chemotherapy appears to be a rational approach to patients with LGG who require post-surgical treatment which produces results that appear to be superior to treatment with primary radiotherapy(RT). Further, this approach makes RT available for those who progress and, by avoidance of RT, may allow a better quality of life for survivors.

Notes: presented in Nov 2010 in Montreal, Canada at annual meeting of Society for Neuro-Oncology(SNO); June 2012 Maui, Hawaii, Rocky Mountain Neurological Society. Click here for full text of the abstract.


Primary Treatment of Low Grade Glioma with Multi-agrent Chemotherapy


Introduction

    Between 1995 and 2012 we treated 64 patients with low grade gliomas (LGG). Median follow-up is 79 months, mean 75 months, and range 14-196. There were 17 astrocytomas, 32 oligodendrogliomas (ODG), and 15 mixed tumors. Of 37 patients whose tumors were tested for 1p19q co-deletion, 23 were positive. 52 patients were treated with primary chemotherapy, and 12 received no post-surgical treatment. We report the results of this large group of patients with LGG treated by a single investigator with primary chemotherapy.


Methods

    Based on the fact that cancer is seldom, if ever, curable with single agent chemotherapy, we chose to create a hybrid regimen (mPCV) which combines temozolomide (TMZ) the current standard, with PCV (minus procarbazine) the excessively toxic regimen first shown to be effective in LGG


Results

    52 patients were treated with primary chemotherapy. This regimen was well tolerated; there were no treatment related deaths and 1 patient was hospitalized with shingles. The mean number of monthly courses of mPCV was 12, (range 1-20). Of 632 monthly courses, there were 73 episodes (12%) OF grades III/IV leukopenia and 40 episodes (6%) of grades III/IV thrombocytopenia. Of 52 patients treated, 16 have relapsed. One progressed at 31 months with GBM and died. The next earliest death occurred at 49 months and the latest at 132. All whose tumors recurred as GBM (9) died. The other 7 have responded to salvage therapy including radiotherapy (RT). Overall survival is 84% and relapse-free survival is 70%. Analysis of survival as a function of tumor type indicates that only 1 of 9 deaths occurred among 23 patients who tested positive for 1p19q co-deletion. Objective response to treatment does not appear to predict outcome.


Conclusions

    Follow-up is too brief to predict median survival. Nevertheless, we can conclude that primary chemotherapy appears to be rational and our results appear to be strikingly superior to patients reported from the Mayo Clinic who were predominantly treated with radiation versus our chemotherapy approach. (for graphical representation of comparative results, please see this page) Further, this approach preserves RT for relapses and, by avoiding RT, offers a better quality of life for survivors.