Avastin and CPT-11; a promising combination therapy for glioblastoma multiforme
James Need, Ph.D.
Note: The author of this paper is not an M.D. The contents of this paper are based on the listed references and are offered for educational and informational purposes only. This article is meant to bring attention to a timely treatment therapy that should be considered; it is not meant to be a complete literature review for either agent. Patients should refer to their health care provider for medical advice.
Note from Al Musella, DPM 3/2/2008: Recent evidence points to the use of Avastin alone may be as good as the combinations. Other drugs besides cpt-11 are being tried with good results. Trials are ongoing - but I just wanted to make you aware that there are now more options.
In October, 1998, CPT-11 (Irinotecan) received full FDA approval for metastatic colon cancer that had recurred or spread following treatment with standard chemotherapy. CPT-11 inhibits topoisomerase I, an enzyme that relaxes supercoiled DNA during replication and transcription. Binding of CPT-11 to this enzyme stabilizes topoisomerase I and DNA. When advancing replication enzymes collide with the drug-topoisomerase I-DNA complex, double stranded DNA breaks occur that result in tumor cell death. In the late 90’s, CPT-11 showed promising results in preliminary pre-clinical and clinical trials for brain tumor treatment (1). Ensuing clinical trials with CPT-11 showed activity for adult patients with recurrent malignant glioma (2); pediatric patients with high risk malignant brain tumors (3, 4); and in combination with BCNU (5, 6), and Temozolomide (7, 8, 9, 10).
Avastin (bevacizumab) is a therapeutic, recombinant, humanized antibody designed to specifically inhibit vascular endothelial growth factor or VEGF, a protein that plays a major role in angiogenesis and the maintenance of existing blood vessels throughout the life cycle of a tumor. By inhibiting VEGF, Avastin is designed to interfere with the blood supply to a tumor, which is thought to be critical to a tumor's ability to grow and spread in the body. In 2002, phase 3 clinical trials were undertaken against several cancer types to establish the efficacy of Avastin (11). Avastin was approved by the FDA in February 2004, as a first line treatment for metastatic colorectal cancer and was further approved in October 2006, in combination with carboplatin and paclitaxel for the first-line treatment of patients with unresectable, locally advanced, recurrent or metastatic, non-squamous, non-small cell lung cancer (12, 13). Such was the potential of Avastin and the anti-VEGF concept that it was readily tried against numerous more challenging cancers.
CPT-11 and Avastin
In November, 2005, Vance reported that Avastin and CPT-11 combination therapy demonstrated rapid clinical and radiographic improvement in patients with relapsed malignant glioma. Furthermore, some patients achieved long term improvement (14). Early in 2006, Pope et al. reported that MRI scans of recurrent glioma patients treated with Avastin and CPT-11 (as well as carboplatin and etopside) showed “remarkable” and rapid contrast-enhancing tumor shrinkage (15). At almost the same time Vredenburgh et al. reported Avastin and CPT-11 an effective treatment for recurrent glioblastoma multiforme with moderate toxicity. The 6-month progression-free survival among all patients was 46% and the 6-month overall survival was 77% (16). In February 2007, Gonzalez et al. concluded that Avastin alone and in combination with other agents reduced radiation necrosis by decreasing capillary leakage and the associated brain edema (17). In June 2007, Raval et al. reported the combination of Avastin and CPT-11 was well tolerated, safe, and significant improvements in cognitive functional and functional status were demonstrated (18). That same month, Friedland et al. reported that the Avastin and CPT-11 combination was safe and had excellent activity in a relapsed, heavily pre-treated population of patients with high grade malignant glioma – most of whom would not be candidates for clinical trials (19). Kang et al. also reported the above combination improved 6 month progression-free survival when compared to historical figures (20). In a very recent editorial review of new glioma treatments, Omuro and DeLattre noted that the Avastin and CPT-11 combination was the single positive targeted therapy to date. However, results of randomized trials need to be completed (21). While this combination therapy is by no means a cure, Friedman makes it clear when he states “ the classical wisdom of utilizing multiple chemotherapeutic agents with non-overlapping toxicity and independent mechanism of action unequivocally is producing an ever increasing cohort of patients for whom GBM is not a terminal event (22).”
Below are the scans of a 75 year old woman with a GBM. The first scan was taken prior to beginning Avistan/CPT-11 and the remaining scans show the progress over a 12 month period. (She generously released these for informational purposes.) Of course these results are not representational of all individuals treated with Avistan/CPT-11 but do indicate one individual with a very positive outcome.
Special acknowledgement is made to the Health Clinic Students of the Albany Law School for their efforts in winning an insurance appeal for Avastin/CPT-11 combination therapy. Their research was very useful in developing this review. For more information on fighting insurance denials for Avastin/CPT-11 see http://www.albanylaw.edu/sub.php?navigation_id=1454 and contact the Musella Foundation.
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