The proponents of this novel therapy argue that this feature of proton Beam radiotherapy justifies its use. However, there are other ways to spare normal tissue, including: Three-dimensional conformal radiation therapy (3D-CRT. Intensity modulated radiation therapy (IMRT), Conformal proton beam radiation therapy, Stereotactic radiosurgery/stereotactic radiotherapy and  Brachytherapy (internal radiotherapy). In addition, the claim that safety alone is the reason to adopt proton beam for routine use should not be made in the absence of studies that confirm better outcomes.  Because proton beam technology is available on only a number of US facilities and because craniospinal radiation  is not performed very frequently, studies to support the assertion that proton beam radiotherapy is superior have not been done and the treatment should still be considered investigational.

Proton beam therapy systems are approved by the FDA 510(k) process as a “medical device designed to produce and deliver a proton beam for the treatment of patients with localized tumors and other conditions susceptible to treatment by radiation” (FDA, 2006). Examples of such systems are the Optivus Proton Beam Therapy System (Optivus Technology Inc., Loma Linda, CA) and the IBA Proton Therapy System-Proteus 235 (Ion Beam Applications S.A., Philadelphia, PA).

The Agency for Healthcare Research and Quality published a 2009 technology report on particle beam radiation therapies for the treatment of cancers including skull base and brain tumors. They noted that there is a proposed advantage of using particle beam therapy, including PBT, where precise radiation targeting is critical in tumors of the skull base and tumors adjacent to the brain and brain stem. The report concluded that studies on charged particle therapy “do not document the circumstances in contemporary treatment strategies in which radiotherapy with charged particles is superior to other modalities. Comparative studies in general, and randomized trials in particular (when feasible) are needed to document the theoretical advantages of charged particle radiotherapy to specific clinical situations”.

In a technology assessment on the use of PBT for the treatment of cancer, the Australia and New Zealand Horizon Scanning Network (2006) stated that PBT “may be of particular benefit” in the treatment of patients with intermediate depth tumors such as those in the head, cancers that are located in difficult or dangerous-to-treat areas, and tumors in locations where “conventional radiotherapy would damage surrounding tissue to an unacceptable level” (e.g., central nervous system and head). PBT “may be ideal for use in the treatment of pediatric patients where the need to avoid secondary tumors is important due to the potentially long life span after radiation treatment when they may develop radiation induced malignancies. It is not clear how this may relate to cranio-spinal radiation.

Y. Lievens, W. den BogaertProton beam therapy: Too expensive to become true?. Radiotherapy and Oncology, Volume 75, Issue 2, Pages 131-133 2005

Yock TI, Tarbell NJ.Technology insight: Proton beam radiotherapy for treatment in pediatric brain tumors. Nat Clin Pract Oncol. 2004 Dec;1(2):97-103;

Semenova J.Proton beam radiation therapy in the treatment of pediatric central nervous system malignancies: a review of the literature. J Pediatr Oncol Nurs. 2009 May-Jun;26(3):142-9. Epub 2009 May 21.

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

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In a 2008 review of atypical and anaplastic-meningiomas by Yang et al, the mean overall survival for atypical meningiomas was found to be 11.9 years vs. 3.3 years for anaplastic meningiomas. Mean relapse-free survival for atypical meningiomas was 11.5 years vs. 2.7 years for anaplastic meningiomas. Meningiomas are often vascularized tumors and and it is reasonable to consider antiangiogenic therapy for meningioma. In particular, malignant meningiomas produce high levels of vascular endothelial growth factor (VEGF) and the Avastin blocks this growth factor. It would make sense that Avastin should be effective. However, agressive and anaplastic  meningiomas are rare and there is little known about what works and what does not work for it. Chamberlain found that temozolamide appears ineffective for refractory meningioma. Hydroxyurea is more promising.

Angiogenesis inhibitors, progestins, agents that target fundamental cell signaling pathways, somatostatin analogues, and a variety of other molecular treatments are being investigated.

Norden AD, Drappatz J, Wen PY. Advances in meningioma therapy.Curr Neurol Neurosci Rep. 2009 May;9(3):231-40.

Yang SY et al.: Atypical and anaplastic meningiomas: prognostic implications of clinicopathological features. J Neurol Neurosurg Psychiatry. 2008 May;79(5):574-80.

S. Goutagny et al, Radiographic regression of cranial meningioma in a NF2 patient treated by bevacizumab Ann Oncol (2011) 22(4): 990-991

Chamberlain MC, Tsao-Wei DD, Groshen S. Temozolomide for treatment-resistant recurrent meningioma.Neurology. 2004 Apr 13;62(7):1210-2.

Newton HB. Hydroxyurea chemotherapy in the treatment of meningiomas. Neurosurg Focus. 2007;23(4):E11.

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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

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How to follow a patient with treated brain metastases is becoming a more and more actual clinical problem as treatments that control systemic disease continue to improve. It is not uncommon now to follow a patient for many months or even years after treatment of metastatic disease without new metastases developing. One study reported a median time of 8.8 months to new metastasis after radiosurgery. Patients with 3 or more lesions and cancer histologies other than NSCLC were more likely to have additional future metastasis. This data produced a recommendation for close surveillance with a 3-month interval between magnetic resonance imaging (MRI), in order to identify new metastasis early to facilitate the most effective treatment. However, the most appropriate frequency and choice of imaging modality following treatment of a patient with brain metastases remain controversial. As the most sensitive current imaging modality for the brain, MRI is the preferred imaging modality, even with an  newer applications such as spectroscopy, diffusion-weighted imaging, and perfusion-weighted imaging.

A. Mintz, MD et al,  Management of single brain metastasis: a practice guideline. Curr Oncol. 2007 August; 14(4): 131–143.

Patel SH, Robbins JR, Videtic GM, Gore EM, Bradley JD, Gaspar LE, Germano I, Ghafoori P, Henderson MA, Lutz ST, McDermott MW, Patchell RA, Robins HI, Vassil AD, Wippold FJ II, Expert Panel on Radiation Oncology-Brain Metastases. ACR Appropriateness Criteria® follow-up and retreatment of brain metastases. [online publication]. Reston (VA): American College of Radiology (ACR); 2011. 8 p. [33 references]

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There are several ongoing studies for lung cancer. For breast cancer, there is also a study:  Irinotecan and Temozolomide in Treating Patients With Breast Cancer Who Have Received Previous Treatment for Brain Metastases, NCT00617539.

 nccn.org, brain cancers, p.38

 Chou R, Chen A, Lau D.Complete response of brain metastases to irinotecan-based chemotherapy.ONCOLOGY. Vol. 22 No. 2

Majores M, von Lehe M, Fassunke J, Schramm J, Becker AJ, Simon M. Tumor Recurrence and Malignant Progression of Gangliogliomas. Cancer. 2008;113:3355-3363. Available at: http://www.ncbi.nlm.nih.gov/pubmed/18988291. July 7, 2011.

DeMarchi R, Abu-Abed S, Munoz D, Loch Macdonald R. Malignant ganglioglioma: case report and review of literature. Journal of Neuro-oncology. 2011;101:311-318

Ajay Pandita, Anandh Balasubramaniam, Richard Perrin, Patrick Shannon and Abhijit Guha Malignant and benign ganglioglioma: A pathological and molecular study Neuro Oncol (April 2007) 9 (2): 124-134.

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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

Evans DG, Baser ME, McGaughran J, Sharif S, Howard E, Moran A. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet 2002;39:311-4.

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