For the vast majority of patients, monotherapies for brain tumors have not generally been found highly effective.  This is certainly the case with targeted agents such as receptor tyrosine kinase (RTK) inhibitors (see O'Reilly 2002, Faivre et al 2006, de Groot and Gilbert 2007, and summary of Stommel et al 2007), and is mostly the case with cytotoxic chemotherapies as well.

A minority of patients do benefit from particular monotherapies, such as certain targeted agents, and tumor molecular testing can be used to help identify which treatments might be effective (or not) for each patient.  For further information, see individualized treatment.

Due to disappointing results from monotherapy, the trend in neuro-oncology (and oncology in general) is increasingly towards use of combination treatments ("cocktails") (see Linskey 2000, Williams 2002, Lassman and Holland 2005 (especially last two paragraphs), Sporn 2006, Williams 2008, Debinski 2008, and TCGA 2008).  It has even been asserted that use of monotherapy is "nihilistic, inappropriate, and clearly going to be unsuccessful" (Friedman 2007).

Mounting evidence from many studies indicates that monotherapies fail mainly because tumors use multiple redundant pathways to survive and grow (see references above and tumor robustness), whereas monotherapies target only one pathway or a limited subset of pathways, sometimes also with limited effect on each pathway (eg, due to toxicity limitations on dosages, imperfect affinity to targets, and innate drug resistance mechanisms such as drug efflux pumps).  As a result, tumors are routinely able to "bypass" the effect of monotherapies, and this resistance to treatment can increase over time due to tumor evolution; moreover, treatments themselves can promote faster tumor evolution, leading to treatment resistance and also increased malignancy upon tumor recurrence (see TCGA 2008).  The aim of combination treatment is therefore to use a complementary set of treatments which together (a) target most or all pathways associated with tumor survival and growth, in an additive or synergistic manner, (b) reduce the likelihood of development of treatment resistance due to tumor evolution, and (c) avoid excessive toxicity to normal tissues.

Many treatments can probably be combined without significant risk if (a) proper dosages (individualized to each patient) are used, (b) possible overlapping toxicities and adverse interactions are reviewed (see Scripture and Figg 2006), and (c) side effects are closely monitored.

Although the hypothesis is currently under debate, it may also be the case that tumor stem cells play a significant, or even primary, role in causing ineffectiveness of treatment and tumor recurrence.  See tumor stem cells for further information.  

Although radiotherapy is routinely combined with daily TMZ in treatment of GBM, there is considerable evidence that adding other cytotoxic and cytostatic agents to radiotherapy can further increase efficacy.  For a discussion of this "concurrent chemoradiation" approach, see Seiwert et al 2006, and also Stupp et al 2007, Kim and Tannock 2005, and an extensive list of radiosensitizers.  See Narayana et al 2008 for a small study which combined radiotherapy with Avastin (bevacizumab) and TMZ for newly diagnosed GBM.

Since most patients receive only one course of radiotherapy, it is important that maximum benefit be derived from this "one-time" opportunity, and concurrent chemoradiation may be the best available option for doing so.  The importance of this is further heightened by the fact that radiotherapy usually follows shortly after surgical tumor resection, when tumor bulk has been reduced and subsequent treatment has increased opportunity to be effective.   

Combining Targeted Treatments

For a general discussion on strategies for combining targeted treatments, see Dancey and Chen 2006.

Multi-Agent Cytostatic Treatment

For a discussion of a "complementary, multi-agent, low-toxicity, chronic, cytostatic therapeutic approach to treating patients with gliomas," see Linskey 2000.  Patients with low-grade gliomas are described as the "most logical target group" for this approach.  However, the approach may also be beneficial for patients with high-grade gliomas (via reduction in tumor growth rate), perhaps especially in combination with cytotoxic or other treatments.

In his PhD dissertation, Failly 2007 performed theoretical and in vitro studies for GBM and found that not only were combination treatments necessary, but also that only specific combinations were effective, involving combinations of cytotoxic and cytostatic agents, as well as specific combinations of multiple targeted cytostatic agents (see pp. 3 and 61).  Also see Kim and Tannock 2005.

When combining cytotoxic and cytostatic treatments, patients may wish to consider pausing the cytostatic treatment during the days of taking the cytotoxic treatment, particulary for cytotoxic treatments which target dividing tumor cells, such as radiotherapy and most chemotherapies (since cytostatic treatment would be expected to inhibit cell division).

For example, on the 5/23 schedule of TMZ, one might take TMZ on days 1-5, nothing on day 6, cytostatic treatments on days 7-27, nothing on day 28, then repeat. However, it is emphasized that there is currently no consensus regarding whether it is best to pause or not pause cytostatic treatment in this way. The best approach may depend on the specific cytotoxic and cytostatic agents involved, in which case it may not be possible to formulate a general rule for this issue. For further information, see Kim and Tannock 2005.

Combining Anti-angiogenic and Other Antitumor Agents

Preliminary clinical data indicates that the antiangiogenic agent Avastin (bevacizumab) may offer benefit as a monotherapy for recurrent GBM for some patients, however sufficient overall survival data is not yet available.  See Narayana et al 2008 for a small study which combined radiotherapy with Avastin (bevacizumab) and TMZ for newly diagnosed GBM.

For a general discussion related to combining antiangiogenic agents with other antitumor agents, see Gasparini et al 2005.  For a discussion of anti-angiogenic effects of metronomic chemotherapy, and strategies for combining metronomic chemotherapy with other anti-angiogenic agents (eg, Avastin), see Kerbel and Kamen 2004 and Emmenegger and Kerbel 2007.

Combining Immunotherapy with Other Agents

Prendergast and Jaffee 2007  tie together concepts from tumor cell genetics, microevironment, inflammation, and immunology.  Three key ideas proposed are: (1) "therapeutic strategies that fail to harness the immune system will always be defeated by tumor resistance, due to the large 'genomic space' that genetically plastic tumor cells can readily access to evolve resistance mechanisms,"  (2) "using molecular targeted agents to reverse tumoral immune suppression may offer a powerful method to leverage the efficacy of most if not all therapeutic agents," and "smoldering" inflammation may be related to tumoral immunosuppression, and (3) "by ablating immunosuppression mechanisms, cytotoxic chemotherapy might synergize with, rather than antogonize, active immunotherapy."  See tumor immunotherapy for further information.

Specific Treatment Combinations

Some specific treatment combinations are included in the lists in this website, including a hypothetical "super" cocktail described in Section 5.1.