Villano JL, Seery TE, Bressler LR: Temozolomide in malignant gliomas: current use and future targets. Cancer Chemother Pharmacol 64 (4): 647-55, 2009.

For Lay version see here

Glioblastoma Multiforme is a disease in which significant progress has been achieved over the past two decades and much investigation of novel drugs in ongoing. One such drug that has been extensively studied is thalidomide.  An early study(Marx et al) assessed 38 patients for response. Two patients (5%) achieved a partial response and 16 (42%) had stable disease. The median survival was 31 weeks and the 1-year survival was 35%. Patients who had a partial response or stable disease had either a stabilization or improvement in quality of life scores or performance status. It appears that thalidomide has some activity as a single agent and that it can be increased by combining it with other drugs. One combination that has demonstrated activity is thalidomide and temozolamide and combining thalidomide and irinotecan is also promising. A variety of novel drugs is in trials with thalidomide.

Marx GM, Pavlakis N, McCowatt S, Boyle FM, Levi JA, Bell DR, Cook R, Biggs M, Little N, Wheeler HR. Phase II study of thalidomide in the treatment of recurrent glioblastoma multiforme. J Neurooncol. 2001 Aug;54(1):31-8.

Olson JJ, Fadul CE, Brat DJ, Mukundan S, Ryken TC. Management of newly diagnosed glioblastoma: guidelines development, value and application. J Neurooncol. 2009 May;93(1):1-23.

David A. Reardon and Patrick Y. Wen, Therapeutic Advances in the Treatment of Glioblastoma: Rationale and Potential Role of Targeted Agents, The Oncologist February 2006 vol. 11 no. 2 152-164

M. RIVA et al, Temozolomide and Thalidomide in the Treatment of Glioblastoma Multiforme Anticancer Research March-April 2007 vol. 27 no. 2 1067-1071

nccn.org, glioblastoma, 2012

For Lay version see here

REFERENCES:
Siew-Ju See, MRCP (UK), Mark R Gilbert Chemotherapy in Adults with Gliomas  Ann Acad Med Singapore 2007;36:364-9

nccn, Centeral Nervous System, 2012

Mei-Yin C. Polley, Kathleen R. Lamborn, Susan M. Chang, Nicholas Butowski, Jennifer L. Clarke and Michael Prados
Six-month progression-free survival as an alternative primary efficacy endpoint to overall survival in newly diagnosed glioblastoma patients receiving temozolomide Neuro Oncol (2010) 12 (3): 274-282.

For Lay version, see here

Capecitabine (Xeloda) is a drug that damages the DNA (deoxyribonucleic acid) of tumor cells and blocks the function of DNA and RNA (ribonucleic acid) of tumor cells. These actions help to kill the tumor cells. Celecoxib is a drug that may help to prevent the development of some types of cancer by blocking a type of enzyme (COX-2) that is found in tumor cells. Temozolomide and CCNU are the current standard treatment for malignant brain tumors. Both drugs work by damaging the DNA (deoxyribonucleic acid) of tumor cells to kill these tumor cells. 6-Thioguanine is a drug that helps to increase the effects of Temozolomide and CCNU on tumor cells.

This study, NCT00504660, has the following objectives:
Primary Objectives:

To determine the efficacy, as measured by 12 month progression-free survival, of Temozolomide or CCNU with 6-Thioguanine followed by Capecitabine and Celecoxib in the treatment of patients with recurrent and/or progressive anaplastic gliomas or glioblastoma multiforme.
To determine the long-term toxicity of Temozolomide or CCNU with 6-Thioguanine followed by Capecitabine and Celecoxib in recurrent anaplastic glioma or glioblastoma multiforme patients treated in this manner.
To determine the clinical relevance of genetic subtyping tumors as a predictor of response to this chemotherapy and long term survival.

However, the question is about Xeloda alone. I understand that the otehr drugs have been approved.

Xeloda is also being investigated with radiation and in combination with other chemotherapy drugs for glioblastoma. Several trials are lsited on: http://clinicaltrials.gov/ct2/results?recr=Open&term=glioma

http://clinicaltrials.gov/ct2/show/NCT00504660?term=glioma&recr=Open&rank=12

nccn.org, brain cancer

A. Reardon, Patrick Y. Wen Therapeutic Advances in the Treatment of Glioblastoma: Rationale and Potential Role of Targeted Agents The Oncologist, Vol. 11, No. 2, 152-164, February 2006

Jeremic B, Grujicic D, Jevremovic S, Stanisavljevic B, Milojevic L, Djuric L, Mijatovic L. Carboplatin and etoposide chemotherapy regimen for recurrent malignant glioma: a phase II study.J Clin Oncol. 1992 Jul;10(7):1074-7

E Franceschi et al, Phase II trial of carboplatin and etoposide for patients with recurrent high-grade glioma, British Journal of Cancer (2004) 91, 1038-1044.

The Avastin application to the FDA was based on a Phase II clinical trial (BRAIN) in previously treated glioblastoma that evaluated Avastin as a single agent or in combination with irinotecan chemotherapy. When Avastin was evaluated as a single agent, the study showed that at six months 43 percent of patients lived without their disease advancing, as defined by progression-free survival (PFS). In the study, 28 percent of patients responded to Avastin, meaning tumors decreased in size by at least 50 percent. Patients receiving Avastin had a median overall survival of 9.3 months, a secondary endpoint in the study. Most adverse events related to Avastin in this trial appeared to be similar to those previously reported in other Avastin studies. The most common severe (Grade 3 or greater) toxicities in the Avastin-only arm were hypertension (8 percent) and convulsion (6 percent). There were two deaths associated with adverse events in the Avastin-only arm. These data, along with those from the combined Avastin and irinotecan study arm, were presented at the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO).

Avastin is now FDA indicated for the treatment of glioblastoma with progressive disease following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin.

A. Reardon, Patrick Y. Wen Therapeutic Advances in the Treatment of Glioblastoma: Rationale and Potential Role of Targeted Agents The Oncologist, Vol. 11, No. 2, 152-164, February 2006

Stark-Vance V. Bevacizumab and CPT-11 in the treatment of relapsed malignant glioma. Neurooncol 2005;7:369.

Cloughesy T, et al “A phase II, randomized, non-comparative clinical trial of the effect of bevacizumab (BV) alone or in combination with irinotecan (CPT) on 6-month progression free survival (PFS6) in recurrent, treatment-refractory glioblastoma (GBM)” J Clin Oncol 26: 2008; May 20 suppl; Abstract 2010b.

nccn.org, brain cancers, p.38

RTOG is conducting a study of dasatinib with radiation. In its consent it says: “Dasatinib is an investigational agent for the treatment of glioblastoma, although it has been approved by the Food and Drug Administration for another cancer type.”

Vanessa Milano, Yuji Piao, Tiffany LaFortune and John de Groot Dasatinib-induced autophagy is enhanced in combination with temozolomide in glioma Mol Cancer Ther February 1, 2009 8, 394

Du et al. Bead-based profiling of tyrosine kinase phosphorylation identifies SRC as a potential target for glioblastoma therapy. Nature Biotechnology. DOI:10.1038/nbt.1513.

Prior to this approval, only BCNU was approved for adjuvant therapy but, because of its significant toxicity, it was not widely used.

There is strong support for its use in oligodendoglioma, replacing the older (and less well-tolerated) PCV (Procarbazine-Lomustine-Vincristine) regimen. It is also supported off-label for melanoma.

The use of Temodar for glioblastoma has impacted on the overall prognosis. Data from the Surveillance, Epidemiology, and End Results (SEER) Program was analyzed to compare survival of adult glioblastoma patients diagnosed from 2000-2003 to patients diagnosed from 2005-2008, in order to evaluate pre-temozolomide and post-temozolomide periods. The Kaplan-Meier method and Cox proportional hazards models were used. 6,673 patients with glioblastoma diagnosed from 2000-2003 and 7,259 patients diagnosed from 2005-2008 were identified. Median survival times of all patients diagnosed in the 2000-2003 and 2005-2008 periods were 8.1 and 9.7 months, respectively. Amongst patients treated with surgery and a radiation-containing regimen, median survival was 12.0 months in 2000-2003 and 14.2 months in 2005-2008. In the temozolomide era, median survival times ranged from a high of 31.9 months in patients age 20-29 to a low of 5.6 months in patients age 80 and older. The survival of patients with newly diagnosed glioblastoma improved from 2000-2003 to 2005-2008, likely due to temozolomide use. However, median survival time after glioblastoma diagnosis in the SEER population remains well under one year, largely driven by poor prognosis in elderly patients.
nccn.org, brain cancer, 2012

Johnson DR, O’Neill BP. Glioblastoma survival in the United States before and during the temozolomide era.J Neurooncol. 2011 Nov 2.
Lam N, Chambers CR. Temozolomide plus radiotherapy for glioblastoma in a Canadian province: Efficacy versus effectiveness and the impact of O6-methylguanine-DNA-methyltransferase promoter methylation.J Oncol Pharm Pract. 2011 Nov 7.

Despite optimal treatment, the prognosis of patients with malignant gliomas remains poor. Patients with glioblastoma multiforme have a median survival of 9 to 14 months, whereas those with anaplastic astrocytomas have a median survival of 24 to 36 months. Once patients develop tumor progression, conventional chemotherapy is generally ineffective, with a median time to tumor progression of 9 to 13 weeks. There is a need for more effective therapies.
Tyrosine kinases play a fundamental role in signal transduction, and deregulated activity of these enzymes has been observed in an increasing number of cancers. There is growing evidence that specific inhibitors of these tyrosine kinases have potential therapeutic applications in oncology and Gleevec is being actively investigated in this disease. in one phase II component, the 6M-PFS for glioblastoma multiforme patients was 3%, whereas that for anaplastic glioma was 10%. In comparison, a retrospective review of negative phase II trials in recurrent malignant gliomas from the M.D. Anderson Cancer Center found a 6M-PFS of 15% for glioblastoma multiforme and 31% for anaplastic glioma. The results are especially disappointing for anaplastic gliomas where the relative importance of PDGF raised the possibility of potential benefit from imatinib.

The European Organization for Research and Treatment of Cancer and the North Central Cancer Treatment Group are also conducting phase II studies of imatinib in recurrent gliomas. In the European Organization for Research and Treatment of Cancer study, glioblastoma multiforme and anaplastic glioma patients were initially treated with imatinib at a dose of 300 mg twice daily, increasing after 8 weeks to 400 mg twice daily if no grade II toxicity was observed. Subsequently, the protocol was amended to treat patients initially with 400 mg imatinib twice daily, increasing to 500 mg twice daily if no toxicity was observed after 8 weeks. The majority of these patients were on EIAED, and there was no attempt to adjust the dose according to the type of AED. Preliminary results of the European Organization for Research and Treatment of Cancer phase II study in glioblastoma multiforme patients showed 3 partial response and 5 stable disease over 6 months in 51 patients, with a 6M-PFS of 15.7%. In anaplastic glioma patients, there was only 1 partial response in 36 anaplastic oligodendroglioma/anaplastic oligoastrocytoma patients and 1 partial response in 25 anaplastic astrocytoma patients. These results are consistent and suggest that imatinib has minimal single-agent activity in malignant gliomas.

The next step was studying Gleevec in combiantion with other drugs. As an example of the trend, I will focus on Gleevec and Hydrea data. Researchers from Germany have reported clinical benefit in 57% of patients with refractory glioblastoma multiforme treated with Gleevec (imatinib) and hydroxyurea. The details of this phase II study appeared in the September 2005 issue of Annals of Oncology. The current trial included 30 patients with progressive glioblastoma multniorme refractory to chemotherapy and radiation therapy. The combination of Gleevec and hydroxyurea led to a 20% response rate and a disease stabilization rate of 37%. The median time to disease progression was 10 weeks and the overall survival was 19 weeks. Three patients continue on therapy for 106 or more weeks. The two-year progression-free survival was 16% with 32% of patients surviving at least six months. These authors suggest that this combination shows promise. Clearly much more investigation needs to be done before this combination can be routinely prescribed.

Reardon D, Egorin M, Quinn J, et al. Phase II Study of Imatinib Mesylate Plus Hydroxyurea in Adults With Recurrent Glioblastoma Multiforme. Journal of Clinical Oncology. 2005; 23: 9359

Dresemann G. Imatinib and hydroxyurea in pretreated progressive glioblastoma multiforme: a patient series. Annals of Oncology. 2005;16:1702-1708.
McLaughlin ME, Robson CD, Kieran MW, et al. Marked regression of metastatic pilocytic astrocytoma during treatment with imatinib mesylate (ST0571), Gleevec: a case report and laboratory investigation. Journal of Pediatric Hematology and Oncology . 25:644-648.
Patrick Y. Wen et al, Phase I/II Study of Imatinib Mesylate for Recurrent Malignant Gliomas: North American Brain Tumor Consortium Study 99-08 Clinical Cancer Research Vol. 12, 4899-4907, August 15, 2006
M.P. Omuro, S. Faivre, and E. Raymond
Lessons learned in the development of targeted therapy for malignant gliomas
Mol. Cancer Ther., July 1, 2007; 6(7): 1909 – 1919.

Glioblastoma is a disease for which there were few options available until recently. The past several years brought several new potentially promising treatments and one, Temodar, has been FDA approved for this indication. One of these promising approaches is Avastin and irinotecan. Stark-Vance recently reported that, among 21 patients with recurrent malignant glioma treated with bevacizumab plus irinotecan (Camptosar®; Pfizer Pharmaceuticals), one patient achieved a complete response, eight achieved partial responses, and 11 achieved stable disease. Overall, the regimen was reported as well tolerated, although two deaths occurred on treatment, including one patient with an intracranial hemorrhage and one patient with bowel perforation. A formal, single-arm phase II study of bevacizumab plus irinotecan is being performed at the Preston Robert Tisch Brain Tumor Center at Duke University Medical Center for patients with recurrent malignant glioma. Preliminary analyses of results of this trial reveal that this regimen is well tolerated among malignant glioma patients and is associated with a highly exciting rate of radiographic response. Further investigation of the regimen of bevacizumab plus irinotecan is planned. Currently there are 11 sites nationally to participate in the pivotal clinical trial of bevacizumab and irinotecan (Avastin) in recurrent glioblastoma; this combination has been reported to shrink tumors in 63% of patients with recurrent glioblastoma in one small study.There are also other phase II trials combining Avastin with carboplatin, etoposide and other drugs. In late November 2007, Genetech announced preliminary results of its randomized phase II study with two arms, Avastin vs. Irinotecan/Avastin. The latter arm has a higher TTP and response rate. However, when updated at 2008 ASCO, the Avastin arm had survival of 9.2 months in a bevacizumab-alone group versus 8.7 months with irinotecan, The study is ongoing. There are no reported phase III trials or guideline recommendations for Avastin or Camptosar + Avastin. Avastin alone is in an ongoing phase II trial.

NCCN lists the combination with irinotecan and footnotes it to a 2007 phase II trial. Based on the NCCN recommendation, irinotecan/avastin should not be considered any longer to be investigational, even in the absence of phase III trials; however, because there are no phase III trials, individual insurers may be justified in rejecting NCCN recommendation.

Regarding Avastin alone:

Genentech, Inc. (NYSE: DNA) announced in November 2008 that the company submitted a supplemental Biologics License Application (sBLA) to the U.S. Food and Drug Administration (FDA) for Avastin® (bevacizumab) as a therapy for people with previously treated glioblastoma. If accepted by the FDA, the application would be considered for an accelerated approval that allows provisional approval of medicines for cancer or other life-threatening diseases based on preliminary evidence suggesting clinical benefit.

The Avastin application is based on a Phase II clinical trial (BRAIN) in previously treated glioblastoma that evaluated Avastin as a single agent or in combination with irinotecan chemotherapy. When Avastin was evaluated as a single agent, the study showed that at six months 43 percent of patients lived without their disease advancing, as defined by progression-free survival (PFS). In the study, 28 percent of patients responded to Avastin, meaning tumors decreased in size by at least 50 percent. Patients receiving Avastin had a median overall survival of 9.3 months, a secondary endpoint in the study. Most adverse events related to Avastin in this trial appeared to be similar to those previously reported in other Avastin studies. The most common severe (Grade 3 or greater) toxicities in the Avastin-only arm were hypertension (8 percent) and convulsion (6 percent). There were two deaths associated with adverse events in the Avastin-only arm. These data, along with those from the combined Avastin and irinotecan study arm, were presented earlier this year at the 44th Annual Meeting of the American Society of Clinical Oncology (ASCO).
NCCN has incorporated this regimen into its guideline.

WIth carboplatin: A 2012 study by Readon found that the addition of carboplatin and irinotecan to bevacizumab significantly increases toxicity but does not improve anti-tumor activity to that achieved historically with single-agent bevacizumab among bevacizumab-naïve, recurrent GBM patients. (ClinicalTrials.gov number NCT00953121).

 Glioblastoma: Rationale and Potential Role of Targeted Agents The Oncologist, Vol. 11, No. 2, 152-164, February 2006

Stark-Vance V. Bevacizumab and CPT-11 in the treatment of relapsed malignant glioma. Neurooncol 2005;7:369.

Cloughesy T, et al “A phase II, randomized, non-comparative clinical trial of the effect of bevacizumab (BV) alone or in combination with irinotecan (CPT) on 6-month progression free survival (PFS6) in recurrent, treatment-refractory glioblastoma (GBM)” J Clin Oncol 26: 2008; May 20 suppl; Abstract 2010b.

nccn.org, brain cancers, p.38

Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med. 2005;352:987-996.

Olson JJ, Fadul CE, Brat DJ, et al. Management of newly diagnosed glioblastoma: guidelines, development, value and application. J Neurooncol. 2009;93:1-23.

Reardon DA, Desjardins A, Peters KB, Gururangan S, Sampson JH, McLendon RE, Herndon JE 2nd, Bulusu A, Threatt S, Friedman AH, Vredenburgh JJ, Friedman HS. Phase II study of carboplatin, irinotecan, and bevacizumab for bevacizumab naïve, recurrent glioblastoma.J Neurooncol. 2012 Mar;107(1):155-64.