SNO 2009 Abstracts and ASCO 2009 Abstracts available.

Contents

1. Introduction

2. General Background

3. Treatments with Significant Clinical Data

4. Treatments with Mainly In Vitro and/or Animal Model Data

5. Treatments with Mainly Anecdotal Data and/or Theoretical Rationale

6. Other Resources

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1. INTRODUCTION

Types of Tumors

This website offers information on treatments for consideration of brain tumor patients, especially patients with the

high-grade gliomas such as Glioblastoma Multiforme (GBM) and Anaplastic Astrocytoma. Caution should

be exercised in extrapolating this information to other types of brain tumors.

Selection of Treatments

This website has been developed by Irfan Alvi, moderator of the brain-research group, with input from several group

members. Patients, caregivers, physicians, and researchers are welcome to join the group to discuss treatment options.

The listed treatments are those which are believed to warrant consideration. These lists do not represent medical

advice, and should be regarded only as non-expert opinions. Listed treatments which require further evaluation to

determine whether they should be included in the lists are followed by a question mark (?).

Please do your own research and discuss potential treatments with your doctors and other health care consultants. 

Some of the listed treatments may not make sense for you because of your particular

circumstances. Also, these lists are still under development and are not all-inclusive. There may

be other treatments which are suitable for you which are not listed. Therefore, please do not rely solely

on these lists in order to identify potential treatments. These lists are intended only to be a starting point to help you

in exploring treatment options.

For overviews of treatment options, see Treatment Options for Glioblastoma and other Gliomas (Williams 2009),
Diagnosis and Treatment of High-Grade Astrocytoma (Sathornsumetee et al 2007), and most recently also
Malignant Gliomas in Adults (Wen and Kesari 2008).
 
For a 1-hour audio/slide lecture which overviews mainstream treatment options, see Chamberlain 2008. For more
extensive and in-depth reviews of mainstream treatment options, consisting of interviews with four neuro-
oncologists, see the Malignant Glioma Update 2008 audio program.
 
Categorization of Treatments
 
The listed treatments are divided into three categories based on the types of evidence and rationale which support
them. (For a thought-provoking discussion on validity of published research findings, see Ioannidis 2005,
PLoS Medicine Editors 2005, Wren 2005, Shrier 2005, Pauker 2005, Goodman and Greenland 2007, and
Ioannidis 2007. For related discussion on translation of basic research into clinical practice, see Ioannidis 2006.)
 
Within each of these three categories, the treatments are further divided into "primary" treatments and
treatments which might be added to the primary treatments. Within each of these subdivided categories,
treatments are listed roughly in order of decreasing preference (based mainly on efficacy and safety).
 
Primary treatments are typically cytotoxic treatments which can kill tumor cells and thereby potentially shrink
tumors. Treatments to consider adding tend to be cytostatic treatments aimed at preventing tumor cells from
dividing and proliferating, thereby inhibiting tumors from growing without necessarily shrinking them.
 
However, there is sometimes overlap between cytotoxic and cytostatic effects, and some treatments may work by
both mechanisms to some extent (see Linskey 2000 and Kamb et al 2007). It is therefore perhaps best to think of
primary treatments as being potentially effective enough to form the "core" of a treatment strategy, with added
treatments being intended to improve overall efficacy (potentially substantially).
 
Supplements 
 
Treatments are also divided into categories of supplements and non-supplements. "Supplements" are typically (but
not always) natural compounds, and their defining feature is that they are available without a prescription in the US.
Categorization of a treatment as a supplement should not be presumed to imply anything about its efficacy and
safety, or lack thereof; the available evidence should be reviewed in order to make such judgments. For a
comprehensive discussion on use of natural compounds for cancer treatment, see Boik 2001. Also see
Williams 2002, Wallace 2004, and Williams 2009 for discussions on use of natural compounds focused on brain
tumors.
 
Disclaimer
 
Neither Irfan Alvi nor any other members of the brain-research group accept any liability related to use of this
website for any purpose. Again, none of the content of this website represents medical advice.
 
Dedication
 
This website is inspired by and dedicated to my mother, Zarina Alvi, who developed GBM and passed on in
August 2007, as well as the many other brain tumor patients and caregivers I have come to know on this journey.
 

Suggestions regarding this website are requested and may be sent to Irfan Alvi at iaa@comcast.net.

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2. GENERAL BACKGROUND

SNO 2009 Abstracts and ASCO 2009 Abstracts available.
 

Content for the following topics is being added as this website is developed:

• Beyond Standard Treatment (a message copied from the brain-research group)
• A Personal Perspective on Cancer: Review of "The War on Cancer" (Faguet 2008)
• Conditional survival probabilities, long-term survival, and cure of brain tumors
• Milestones in Cancer Research
• Tumor biophysics
• Tumor carcinogenesis theories 
• Tumor molecular biology
• Characteristic features of gliomas
• Tumor growth
• Tumor metabolism (bioenergetics)
• Tumor evolution
• Tumor stem cells
• Tumor microenvironment
• Tumor invasion 
• Tumor angiogenesis & anti-angiogenic treatment (eg, Avastin)
• Tumor immunotherapy
• Tumor robustness
• Overall treatment strategy 
• Combining treatments
• Tumor chronotherapy
• Glycans
• Diet
• Nutritional supplements
• Antioxidants
• Individualized treatment
• Optimization of treatment dosing and scheduling
• Preventing treatment resistance
• Ending treatment and preventing recurrence
• Tumor imaging

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3. TREATMENTS WITH SIGNIFICANT CLINICAL DATA

3.1 Primary Treatments

• Surgical tumor resection  -  Standard of care.  Maximal "gross total" resection, or at least 80-90% resection, is highly preferable, including repeated resection upon tumor recurrence when feasible (see Martinez et al 2007, Ryken et al 2008, Sanai and Berger 2008, McGirt et al 2009, and Slotman et al 2009).  However, for GBM, resection should be combined with other treatment (to reduce tumor growth rate) in order to gain a meaningful survival benefit (see Mandl et al 2008).  Mangiola et al 2008  have even suggested resection going 1 to 2 cm beyond the tumor border into normal tissue (presumably only in cases without significant risk of causing neurological deficits).  On the other hand, Deisboeck and Guiot 2008 have hypothesized, based on a biomechanical argument, that resection may cause residual tumor cells to be more invasive; if so, that does not necessarily argue against resection, but at least highlights the need for specifically anti-invasive treatment promptly after resection.  For a discussion of potential adverse effects of resection, focusing on breast cancer but possibly also relevant to brain tumors, see Demicheli et al 2008. 
• Novocure-TTF or Novocure-TTF + TMZ  -  In a small single-arm study (Kirson et al 2008) of 10 patients with newly diagnosed GBM, 4 of which had gross total resection, standard radiotherapy + TMZ was followed by Novocure-TTF + TMZ for up to 18 months.  At the end of the study, median survival had reached more than 40 months, with 8 of the 10 patients still alive, and no serious side effects were reported.  Although this is a small study, it is striking that this median survival far exceeds the historical value of about 15 months associated with standard radiotherapy + TMZ, followed by TMZ alone.  In another small study (Kirson et al 2007) of 10 patients with recurrent GBM, using Novocure-TTF without concurrent chemotherapy, a median survival of 62 weeks (after start of treatment) was reported at the end of the study, with 3 of the 10 patients still alive, and no serious side effects were reported.  This median survival is more than double the historical value.
• DC-Vax   -  A dendritic cell vaccine.  See tumor immunotherapy. 
• CDX-110 + TMZ  -  See Sampson et al 2008 for results of combining CDX-110 with 5/23 TMZ and metronomic (daily) TMZ.  Also see tumor immunotherapy. 
• CDX-110  -  A peptide vaccine for EGFR vIII+.  See tumor immunotherapy. 
• Dendritic cell vaccine + Poly-ICLC  -  See tumor immunotherapy. 
• Glioma-Associated Antigen (GAA) Peptide-Pulsed Autologous Dendritic cell vaccine  -  See tumor immunotherapy.  
• Chloroquine + BCNU (carmustine)  -  Three small studies of patients with GBM have been completed, all showing that adding chloroquine to BCNU (carmustine) doubles or triples median survival time compared BCNU alone, making this combination among the best available treatments, especially outside clinical trials.  Median survival time for BCNU alone is comparable to that of TMZ and other standard cytotoxic chemotherapies, and similar survival benefit may be achieved if chloroquine is added to these chemotherapies.   Chloroquine has been widely used for treatment of malaria and other conditions, and can be prescribed off-label at low cost.  See Hagihara et al 2000, Sotelo et al 2000, Reyes et al 2001, Reyes et al 2001, Briceno et al 2003, Sotelo et al 2006, Sotelo et al 2006 (Summary), Toler et al 2006, Briceno et al 2007, and Munshi 2008. 
• TMZ + CCNU (lomustine)  -  In a Phase II study (Herrlinger et al 2006), 31 patients with newly diagnosed GBM were given about 5 cycles of CCNU (100 mg/m^2 on day 1) and TMZ (100 mg/m^2 on days 2 to 6), with dose adjustments and follow-up treatments as necessary, resulting in a median survival of 23 months, with 1 patient (3%) passing away due to septicemia during myelotoxicity, and with 6 patients (19%) experiencing acute but tolerable Grade 4 myelotoxicity.  In a follow-up study (Glas et al 2009), 8 patients were added and given an intensified schedule of about 4 cycles of CCNU (110 mg/m^2 on day 1) and TMZ (150 mg/m^2 on days 2 to 6), again with dose adjustments and follow-up treatments as necessary, resulting in median survival still not reached after 42 months, but with 1 patient (12%) passing away due to septicemia during myelotoxicity, and with 4 patients (50%) experiencing acute but tolerable Grade 4 myelotoxicity.  MGMT promoter methylation status was found to be a very significant prognostic factor.  The results of this protocol, especially the intensified schedule, appear quite promising, but it should be noted that (a) the number of patients (n = 8) on the intensified schedule was small, (b) follow-up treatments after the CCNU/TMZ cycles probably contributed to survival, and (c) toxicity is a concern. 
• Clomipramine  -  See Pilkington application to brain tumors, Rooprai et al 2003, MEN 2005, Levkovitz et al 2005, Parker and Pilkington 2006, Pilkington et al 2008, Donovan 2008, Armstrong 2008, and dosing.  
• Neuradiab  -  I-131 conjugated with a monoclonal antibody targeting tenascin.  See Reardon et al 2008. 
• AP 12009  -  Antisense RNA.  See 2003 Press Release, Hau et al 2006, Schlingenseipen et al 2006, Bogdahn et al 2007, Hau et al 2007, 2007 Phase IIb results, 2008 Phase IIb results, 2008 Phase IIb results, 2008 Phase III Press Release, and Bogdahn et al 2009. 
• Concurrent chemoradiation  -  Combines radiotherapy + concurrent daily cytotoxic chemotherapy (eg, TMZ) + concurrent targeted agents.  See list of radiosensitizers.  Also see combining treatments.
• 3D conformal radiotherapy (or IMRT) + concurrent daily TMZ  -  Standard of care.  Undergoing a second cycle of radiotherapy is currently uncommon, but may be an option for some patients; see Nieder et al 2008.
• TMZ on metronomic (daily) schedule  -  An option for newly diagnosed patients, as well as for patients who experience recurrence on the standard 5/23 TMZ schedule.  See Buttolo et al 2006 for a 6-year Italian GBM study in which metronomic TMZ gave a median survival of 29 months, versus only 12 months with the standard 5/23 TMZ schedule.  While TMZ daily dosage as high as 75 mg/m^2 has been used, lower dosages of about 40 to 50 mg/m^2, or even as low as 20 mg/m^2, provide much lower toxicity, possibly without greatly compromising efficacy.  Also see Kurzen et al 2003, Baruschel et al 2006, Kim et al 2006, Kong et al 2006, Sul et al 2007, Zhou et al 2007, Perry et al 2008, and related abstracts in SNO 2008 (search for "metronomic").  Taken together, these studies suggest that (a) metronomic TMZ may be significantly more effective for newly diagnosed patients as compared to patients with recurrent tumors, and (b) the metronomic TMZ should probably be continued for an extended duration or until recurrence, rather than arbitrarily discontinuing it after a short duration (eg, 6 months).  See Kerbel and Kamen 2004 for a detailed review of metronomic chemotherapy focusing on anti-angiogenic mechanisms, and Emmenegger and Kerbel 2007 for a related follow up.  For comparison, see Wick et al 2009 for a review of various TMZ schedules, emphasizing non-metronomic schedules, and finding that none of these alternative schedules provided substantially better results than the standard 5/23 schedule.  However, as an important precaution related to metronomic TMZ and possibly most or all other treatments which have an anti-angiogenic mechanism, note that Tuettenberg et al 2009 have reported that this treatment (combined with celecoxib) may promote tumor invasion and thereby increase the rate of distant recurrences.  For further information, see Tumor Invasion. 
• TMZ on 5/23 schedule  -  Standard of care.  See Stupp et al 2005 (original paper), Stupp et al 2009 (5-year follow up), and Virtual Trials TMZ links.  For a retrospective analysis which suggests that TMZ should be continued as long as it remains effective in controlling tumor growth (rather than continuing only 6 months after completing radiotherapy, per the Stupp et al protocol), see Anderson and Lindsey 2008; however, note that this analysis has at least two methodological problems: (a) patients with both Grade III and IV gliomas are aggregated together, and (b) only patients who took TMZ for at least 12 months were included in the analysis, thus biasing the results by excluding patients who passed away before 12 months.  See Khasraw et al 2009 for a discussion of three glioma patients who used TMZ between 5 and 8 years with acceptable toxicity; two of the patients experienced recurrence when TMZ was discontinued for a few months, but TMZ was effective for them when restarted.  For a variant of the 5/23 schedule in which TMZ is given twice-daily for the 5 days, see Balmaceda et al 2008; this schedule showed benefit for patients with recurrent gliomas, and may also be beneficial for patients with newly diagnosed gliomas.  See Schaich et al 2008 for discussion of MDR1 genotype as a predictor of response to TMZ. 
• Concurrent radiotherapy + Avastin (bevacizumab) + daily TMZ, followed by Avastin (bevacizumab) + 5/23 TMZ  -  See Narayana et al 2008 for a small study of 14 patients with newly diagnosed GBM which showed 86.7% overall survival at one year, although 3 of the 6 recurrent tumors showed a diffuse pattern.  Also see Lai et al 2008 for a similar small pilot study of 10 patients which showed encouraging progression-free survival, and also provides detailed information on observed toxicities.  See Avastin item below for more information on Avastin. 
• Avastin (bevacizumab)  -  See primarily Tumor Angiogenesis & Anti-Angiogenic Treatment, and also Tumor Invasion and Combining Treatments.
• CCNU (lomustine)  -  See Wolff et al 2008 for a study indicating that CCNU (lomustine) may be generally more effective than BCNU (carmustine).
• Photodynamic therapy (PDT)  -  See Dolmans et al 2003, Eljamel et al 2007, Hu et al 2007, Stummer et al 2007, and Stummer et al 2008.  
• Cotara  -  I-131 conjugated with monoclonal antibody.  Requires convection-enhanced delivery (CED). 
• PCV (Procarbazine + CCNU [lomustine] + Vincristine)  -  See 2008 EMSO report.
• Scorpion Venom Chlorotoxin (I-131 TM601)  -  I-131 conjugated with a chlorotoxin derived from scorpion venom.  See Phase I/II Study and technical description.
• VP-16 (etoposide)
• Stereotactic radiosurgery (SRS)  -  Gamma Knife and Leading Edge are among several available types. 
• Gliadel  -  BCNU wafers implanted surgically.  Provides a substantial survival benefit for (only) a minority of patients.   See Perry et al 2007.
• BCNU (carmustine)
• Sirolimus (rapamycin) or Everolimus (RAD001) or Temsirolimus (Torisel) - See Cloughesy et al 2008.
• Cilengitide (EMD121974)  -  See Reardon et al 2007.
• Gleevec (imatinib) + hydroxyurea  -  See Reardon et al 2005, Desjardins et al 2007, and Shah et al 2007
• TMZ + Poly-ICLC
• Cerepro - See Phase III Results.
• Antineoplastons  -  Controversial, and also very expensive.
• TMZ + Nexavar (sorafenib)  -  See Phase II trial for newly diagnosed GBM and Phase II trial for recurrent GBM.
• Zactima (vandetanib or ZD6474)?

SNO 2009 Abstracts and ASCO 2009 Abstracts available.