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1.  TTFields alone and in combination with chemotherapeutic agents effectively reduce the viability of MDR cell sub-lines that over-express ABC transporters 
BMC Cancer  2010;10:229.
Exposure of cancer cells to chemotherapeutic agents may result in reduced sensitivity to structurally unrelated agents, a phenomenon known as multidrug resistance, MDR. The purpose of this study is to investigate cell growth inhibition of wild type and the corresponding MDR cells by Tumor Treating Fields - TTFields, a new cancer treatment modality that is free of systemic toxicity. The TTFields were applied alone and in combination with paclitaxel and doxorubicin.
Three pairs of wild type/MDR cell lines, having resistivity resulting from over-expression of ABC transporters, were studied: a clonal derivative (C11) of parental Chinese hamster ovary AA8 cells and their emetine-resistant sub-line EmtR1; human breast cancer cells MCF-7 and their mitoxantrone-resistant sub lines MCF-7/Mx and human breast cancer cells MDA-MB-231 and their doxorubicin resistant MDA-MB-231/Dox cells. TTFields were applied for 72 hours with and without the chemotherapeutic agents. The numbers of viable cells in the treated cultures and the untreated control groups were determined using the XTT assay. Student t-test was applied to asses the significance of the differences between results obtained for each of the three cell pairs.
TTFields caused a similar reduction in the number of viable cells of wild type and MDR cells. Treatments by TTFields/drug combinations resulted in a similar increased reduction in cell survival of wild type and MDR cells. TTFields had no effect on intracellular doxorubicin accumulation in both wild type and MDR cells.
The results indicate that TTFields alone and in combination with paclitaxel and doxorubicin effectively reduce the viability of both wild type and MDR cell sub-lines and thus can potentially be used as an effective treatment of drug resistant tumors.
PMCID: PMC2893108  PMID: 20492723
2.  Alternating electric fields (TTFields) inhibit metastatic spread of solid tumors to the lungs 
Tumor treating fields (TTFields) are low intensity, intermediate frequency, alternating electric fields used to treat cancerous tumors. This novel treatment modality effectively inhibits the growth of solid tumors in vivo and has shown promise in pilot clinical trials in patients with advanced stage solid tumors. TTFields were tested for their potential to inhibit metastatic spread of solid tumors to the lungs in two animal models: (1) Mice injected with malignant melanoma cells (B16F10) into the tail vein, (2) New Zealand White rabbits implanted with VX-2 tumors within the kidney capsule. Mice and rabbits were treated using two-directional TTFields at 100–200 kHz. Animals were either monitored for survival, or sacrificed for pathological and histological analysis of the lungs. The total number of lung surface metastases and the absolute weight of the lungs were both significantly lower in TTFields treated mice then in sham control mice. TTFields treated rabbits survived longer than sham control animals. This extension in survival was found to be due to an inhibition of metastatic spread, seeding or growth in the lungs of TTFields treated rabbits compared to controls. Histologically, extensive peri- and intra-tumoral immune cell infiltration was seen in TTFields treated rabbits only. These results raise the possibility that in addition to their proven inhibitory effect on the growth of solid tumors, TTFields may also have clinical benefit in the prevention of metastatic spread from primary tumors.
PMCID: PMC2776150  PMID: 19387848
Tumor treating fields; Metastases; Immune response
3.  An Evidence-Based Review of Alternating Electric Fields Therapy for Malignant Gliomas 
Opinion statement
Glioblastoma is a deadly disease and even aggressive neurosurgical resection followed by radiation and chemotherapy only extends patient survival to a median of 1.5 years. The challenge in treating this type of tumor stems from the rapid proliferation of the malignant glioma cells, the diffuse infiltrative nature of the disease, multiple activated signal transduction pathways within the tumor, development of resistant clones during treatment, the blood brain barrier that limits the delivery of drugs into the central nervous system, and the sensitivity of the brain to treatment effect. Therefore, new therapies that possess a unique mechanism of action are needed to treat this tumor. Recently, alternating electric fields, also known as tumor treating fields (TTFields), have been developed for the treatment of glioblastoma. TTFields use electromagnetic energy at an intermediate frequency of 200 kHz as a locoregional intervention and act to disrupt tumor cells as they undergo mitosis. In a phase III clinical trial for recurrent glioblastoma, TTFields were shown to have equivalent efficacy when compared to conventional chemotherapies, while lacking the typical side effects associated with chemotherapies. Furthermore, an interim analysis of a recent clinical trial in the upfront setting demonstrated superiority to standard of care cytotoxic chemotherapy, most likely because the subjects’ tumors were at an earlier stage of clonal evolution, possessed less tumor-induced immunosuppression, or both. Therefore, it is likely that the efficacy of TTFields can be increased by combining it with other anti-cancer treatment modalities.
PMCID: PMC4491358  PMID: 26143265
Alternating electric fields; Malignant gliomas; Glioblastoma; Review
4.  The effect of field strength on glioblastoma multiforme response in patients treated with the NovoTTF™-100A system 
The NovoTTF™-100A system is a portable device that delivers intermediate frequency alternating electric fields (TTFields, tumor treating fields) through transducer arrays arranged on the scalp. An ongoing trial is assessing its efficacy for newly diagnosed glioblastoma multiforme (GBM) and it has been FDA-approved for recurrent GBM.
The fields are believed to interfere with formation of the mitotic spindle as well as to affect polar molecules at telophase, thus preventing cell division. The position of the four arrays is unique to each patient and optimized based on the patient’s imaging. We present three patients with GBM in whom the fields were adjusted at recurrence and the effects of each adjustment. We believe there may be a higher risk of treatment failure on the edges of the field where the field strength may be lower.
The first patient underwent subtotal resection, radiotherapy with temozolomide (TMZ), and then began NovoTTF Therapy with metronomic TMZ. She had good control for nine months; however, new bifrontal lesions developed, and her fields were adjusted with a subsequent radiographic response. Over the next five months, her tumor burden increased and death was preceded by a right insular recurrence.
A second patient underwent two resections followed by radiotherapy/TMZ and NovoTTF Therapy/TMZ. Six months later, two new distal lesions were noted, and he underwent further resection with adjustment of his fields. He remained stable over the subsequent year on NovoTTF Therapy and bevacizumab.
A third patient on NovoTTF Therapy/TMZ remained stable for two years but developed a small, slow growing enhancing lesion, which was resected, and his fields were adjusted accordingly. Interestingly, the pathology showed giant cell GBM with multiple syncitial-type cells.
Based on these observations, we believe that field strength may play a role in ‘out of field’ recurrences and that either the presence of a certain field strength may select for cells that are of a different size or that tumor cells may change size to avoid the effects of the TTFields.
PMCID: PMC4036833  PMID: 24884522
glioblastoma; tumor treating fields; cytotoxic; NovoTTF therapy; NovoTTF-100A System
5.  Dexamethasone exerts profound immunologic interference on treatment efficacy for recurrent glioblastoma 
British Journal of Cancer  2015;113(2):232-241.
Patients with recurrent glioblastoma have a poor outcome. Data from the phase III registration trial comparing tumour-treating alternating electric fields (TTFields) vs chemotherapy provided a unique opportunity to study dexamethasone effects on patient outcome unencumbered by the confounding immune and myeloablative side effects of chemotherapy.
Using an unsupervised binary partitioning algorithm, we segregated both cohorts of the trial based on the dexamethasone dose that yielded the greatest statistical difference in overall survival (OS). The results were validated in a separate cohort treated in a single institution with TTFields and their T lymphocytes were correlated with OS.
Patients who used dexamethasone doses >4.1 mg per day had a significant reduction in OS when compared with those who used ⩽4.1 mg per day, 4.8 vs 11.0 months respectively (χ2=34.6, P<0.0001) in the TTField-treated cohort and 6.0 vs 8.9 months respectively (χ2=10.0, P<0.0015) in the chemotherapy-treated cohort. In a single institution validation cohort treated with TTFields, the median OS of patients who used dexamethasone >4.1 mg per day was 3.2 months compared with those who used ⩽4.1 mg per day was 8.7 months (χ2=11.1, P=0.0009). There was a significant correlation between OS and T-lymphocyte counts.
Dexamethasone exerted profound effects on both TTFields and chemotherapy efficacy resulting in lower patient OS. Therefore, global immunosuppression by dexamethasone likely interferes with immune functions that are necessary for the treatment of glioblastoma.
PMCID: PMC4506397  PMID: 26125449
dexamethasone; glioblastoma; NovoTTF-100A; tumour immunology; chemotherapy
6.  Long-term survival of patients suffering from glioblastoma multiforme treated with tumor-treating fields 
Glioblastoma multiforme (GBM) is the most common and malignant primary intracranial tumor, and has a median survival of only 10 to 14 months with only 3 to 5% of patients surviving more than three years. Recurrence (RGBM) is nearly universal, and further decreases the median survival to only five to seven months with optimal therapy. Tumor-treating fields (TTField) therapy is a novel treatment technique that has recently received CE and FDA approval for the treatment of RGBM, and is based on the principle that low intensity, intermediate frequency electric fields (100 to 300 kHz) may induce apoptosis in specific cell types. Our center was the first to apply TTField treatment to histologically proven GBM in a small pilot study of 20 individuals in 2004 and 2005, and four of those original 20 patients are still alive today. We report two cases of GBM and two cases of RGBM treated by TTField therapy, all in good health and no longer receiving any treatment more than seven years after initiating TTField therapy, with no clinical or radiological evidence of recurrence.
PMCID: PMC3514151  PMID: 23095807
Glioblastoma multiforme; Recurrent glioblastoma multiforme; Tumor-treating fields; Long-term survival
7.  Resolution of Cystic Enhancement to Add-On Tumor Treating Electric Fields for Recurrent Glioblastoma after Incomplete Response to Bevacizumab 
Case Reports in Neurology  2014;6(1):109-115.
The NovoTTF-100A device emits alternating tumor treating electric fields (TTFields) that interfere with cytokinesis and chromosome segregation during mitosis. Because it has a similar efficacy to cytotoxic chemotherapy, the device has been approved by the United States Food and Drug Administration for the treatment of recurrent glioblastoma. Although bevacizumab has been in use for recurrent glioblastoma, patients who experience incomplete or no response to bevacizumab may be predisposed to early bevacizumab treatment failure. However, the addition of TTFields therapy may augment the efficacy from bevacizumab. We report a patient with recurrent cystic glioblastoma who received add-on TTFields therapy due to an incomplete response to single-agent bevacizumab. After 6 cycles of therapy, a resolution of cystic enhancement was noted, together with reduction of the tumor cyst and resolution of most of the cerebral edema in the surrounding brain. However, the patient also suffered from relapsed disease at locations distant from the original glioblastoma and the corresponding radiation fields received at initial diagnosis. We conclude that combination TTFields and bevacizumab therapy is safe and may be efficacious for patients with recurrent glioblastoma. A further study would be needed to determine the relapse pattern and the distribution of the electric fields in the brain.
PMCID: PMC4025148  PMID: 24847254
Glioblastoma; Alternating electric fields; Response
8.  Tumor Treating Fields Perturb the Localization of Septins and Cause Aberrant Mitotic Exit 
PLoS ONE  2015;10(5):e0125269.
The anti-tumor effects of chemotherapy and radiation are thought to be mediated by triggering G1/S or G2/M cell cycle checkpoints, while spindle poisons, such as paclitaxel, block metaphase exit by initiating the spindle assembly checkpoint. In contrast, we have found that 150 kilohertz (kHz) alternating electric fields, also known as Tumor Treating Fields (TTFields), perturbed cells at the transition from metaphase to anaphase. Cells exposed to the TTFields during mitosis showed normal progression to this point, but exhibited uncontrolled membrane blebbing that coincided with metaphase exit. The ability of such alternating electric fields to affect cellular physiology is likely to be dependent on their interactions with proteins possessing high dipole moments. The mitotic Septin complex consisting of Septin 2, 6 and 7, possesses a high calculated dipole moment of 2711 Debyes (D) and plays a central role in positioning the cytokinetic cleavage furrow, and governing its contraction during ingression. We showed that during anaphase, TTFields inhibited Septin localization to the anaphase spindle midline and cytokinetic furrow, as well as its association with microtubules during cell attachment and spreading on fibronectin. After aberrant metaphase exit as a consequence of TTFields exposure, cells exhibited aberrant nuclear architecture and signs of cellular stress including an overall decrease in cellular proliferation, followed by apoptosis that was strongly influenced by the p53 mutational status. Thus, TTFields are able to diminish cell proliferation by specifically perturbing key proteins involved in cell division, leading to mitotic catastrophe and subsequent cell death.
PMCID: PMC4444126  PMID: 26010837
9.  Effective Treatment of Advanced Human Melanoma Metastasis in Immunodeficient Mice Using Combination Metronomic Chemotherapy Regimens 
Statement of translational relevance
Despite significant efforts over the last two decades aimed at improving the efficacy of standard treatment (maximum tolerated dose (MTD) of dacarbazine), there has been no significant increase in the median survival of patients suffering from metastatic melanoma. Given the lack of success achieved, a rethinking of alternative treatment strategies is needed. Using preclinical models of advanced melanoma metastasis, we show that metronomic chemotherapeutic combinations results in improved survival, which is achieved with minimal toxicity. These results compare favorably with minimal effectiveness achieved by MTD dacarbazine therapy (alone or in combination with other chemotherapeutic agents or a VEGFR-blocking antibody), often accompanied by higher toxicity. Successes in preclinical setting of metastatic breast cancer have led to a clinical trial to examine the efficacy of metronomic therapy. A similar extension of the metronomic chemotherapeutic combinations presented here into the clinical setting of melanoma metastasis may be warranted.
The development of effective therapeutic approaches for treatment of metastatic melanoma remains an immense challenge. Present therapies offer minimal benefit. While dacarbazine (DTIC) chemotherapy remains the standard therapy, it mediates only low response rates, usually of short duration, even when combined with other chemotherapeutic agents. Thus, new therapeutic strategies are urgently needed.
Experimental design
Using a newly developed preclinical model, we evaluated the efficacy of various doublet metronomic combination chemotherapy against established, advanced melanoma metastasis and compared these to the standard maximum tolerated dose (MTD) DTIC (alone or in combination with chemotherapeutic agents or VEGFR-blocking antibody)
Whereas MTD DTIC therapy did not cause significant improvement in median survival, a doublet combination of low-dose metronomic (LDM) vinblastine (Vbl) and LDM cyclophosphamide (CTX) induced a significant increase in survival with only minimal toxicity. Furthermore, we show that the incorporation of the LDM Vbl/LDM CTX combination with a LDM DTIC regimen also results in a significant increase in survival, but not when combined with MTD DTIC therapy. We also show that a combination of metronomic Vbl therapy and a VEGFR2-blocking antibody (DC101) results in significant control of metastatic disease and that the combination of LDM Vbl/DC101 and LDM DTIC induced a significant improvement in median survival.
The effective control of advanced metastatic melanoma achieved by these metronomic-based chemotherapeutic approaches warrants clinical consideration of this treatment concept given the recent results of a number of metronomic-based chemotherapy clinical trials.
PMCID: PMC2743327  PMID: 19622578
melanoma; spontaneous metastasis; vinblastine; cyclophosphamide; DC101; metronomic chemotherapy
Neuro-Oncology  2014;16(Suppl 3):iii12.
BACKGROUND: (blind field). METHODS: We evaluated MRI markers in 84 GBM patients enrolled in phase 2 trials (NCT00305656, NCT00662506) to investigate the mechanisms of tumor response to anti-VEGF treatment. Forty newly diagnosed GBM (nGBM) patients were treated with the oral pan-VEGFR inhibitor, cediranib, in combination with radiation and temozolomide. Fourteen nGBM patients were treated with radiation and temozolomide alone. Thirty recurrent GBM (rGBM) patients were treated with cediranib alone. All patients underwent serial brain MRI scans at uniform time points. RESULTS: In both the nGBM and rGBM cohorts treated with cediranib, increased tumor perfusion was observed in 20/40 and 7/30 patients, respectively. In contrast, in the nGBM cohort not treated with cediranib increased tumor perfusion was observed in 1/14 patients. Increased tumor perfusion was associated with improved overall survival in nGBM (p = 0.040) and rGBM (p = 0.009) patients. Moreover, increased perfusion was associated with improved tumor oxygenation status in patients the nGBM patients treated with cediranib and chemoradiation. These findings are consistent with a recent report in rGBM patients treated with bevacizumab. CONCLUSIONS: Anti-VEGF therapy confers clinical benefit to GBM patients by normalization of tumor vessels. We hypothesize that the subset of GBM subjects who experience increased perfusion and improved tumor oxygenation status after anti-VEGF therapy will derive optimal benefit from concurrent chemoradiation and innate anti-tumor immune mechanisms. MRI techniques may enable early identification of GBM patients most likely to benefit from this expensive, and potentially toxic, class of anti-cancer drugs. SECONDARY CATEGORY: Imaging.
PMCID: PMC4144509
11.  Dose-Dense Temozolomide for Newly Diagnosed Glioblastoma: A Randomized Phase III Clinical Trial 
Journal of Clinical Oncology  2013;31(32):4085-4091.
Radiotherapy with concomitant and adjuvant temozolomide is the standard of care for newly diagnosed glioblastoma (GBM). O6-methylguanine-DNA methyltransferase (MGMT) methylation status may be an important determinant of treatment response. Dose-dense (DD) temozolomide results in prolonged depletion of MGMT in blood mononuclear cells and possibly in tumor. This trial tested whether DD temozolomide improves overall survival (OS) or progression-free survival (PFS) in patients with newly diagnosed GBM.
Patients and Methods
This phase III trial enrolled patients older than age 18 years with a Karnofsky performance score of ≥ 60 with adequate tissue. Stratification included clinical factors and tumor MGMT methylation status. Patients were randomly assigned to standard temozolomide (arm 1) or DD temozolomide (arm 2) for 6 to 12 cycles. The primary end point was OS. Secondary analyses evaluated the impact of MGMT status.
A total of 833 patients were randomly assigned to either arm 1 or arm 2 (1,173 registered). No statistically significant difference was observed between arms for median OS (16.6 v 14.9 months, respectively; hazard ratio [HR], 1.03; P = .63) or median PFS (5.5 v 6.7 months; HR, 0.87; P = .06). Efficacy did not differ by methylation status. MGMT methylation was associated with improved OS (21.2 v 14 months; HR, 1.74; P < .001), PFS (8.7 v 5.7 months; HR, 1.63; P < .001), and response (P = .012). There was increased grade ≥ 3 toxicity in arm 2 (34% v 53%; P < .001), mostly lymphopenia and fatigue.
This study did not demonstrate improved efficacy for DD temozolomide for newly diagnosed GBM, regardless of methylation status. However, it did confirm the prognostic significance of MGMT methylation. Feasibility of large-scale accrual, prospective tumor collection, and molecular stratification was demonstrated.
PMCID: PMC3816958  PMID: 24101040
12.  Temozolomide for the treatment of metastatic melanoma 
Current Oncology  2007;14(1):27-33.
What is the role of single-agent temozolomide in the treatment of patients with metastatic melanoma?
In comparison with single-agent temozolomide, does the addition of interferon-α to temozolomide improve disease-free survival, overall survival, or response rates?
In comparison with single-agent temozolomide, does the addition of thalidomide to temozolomide improve disease-free survival, overall survival, or response rates?
Because of its oral route of administration and its ability to cross the blood–brain barrier, temozolomide is a potentially attractive chemotherapy agent for adult patients with unresectable metastatic malignant melanoma. To provide treatment recommendations for this new agent, the Melanoma Disease Site Group (dsg) of Cancer Care Ontario’s Program in Evidence-Based Care (pebc) decided to review the available literature on single-agent temozolomide and on temozolomide in combination with interferon-α or thalidomide.
Outcomes of interest included response rates, disease-free survival, overall survival, quality of life, and adverse effects.
Evidence was selected and reviewed by two members of the Melanoma dsg and by methodologists. The present practice guideline report was reviewed and approved by the Melanoma dsg, which comprises medical and radiation oncologists, surgeons, and dermatologists. External review was obtained through a mailed survey of Ontario practitioners, the results of which were reflected in revisions to the practice guideline. Final approval of the guideline report was obtained from the Report Approval Panel of the pbec.
Practice Guideline
These recommendations apply to adult patients with unresectable metastatic malignant melanoma.
It is reasonable to use temozolomide at a dose of 200 mg/m2 orally for 5 days every 4 weeks as initial systemic treatment for patients with unresectable metastatic malignant melanoma.
The addition of moderate-dose interferon-α 2b has produced a significantly higher response rate than has single-agent temozolomide in a large randomized phase iii study. However, overall survival was not altered, and grades 3 and 4 hematologic toxicities were higher with the combined treatment. At the present time, the addition of interferon-α to temozolomide is not recommended.
One randomized phase ii study and six other phase ii studies showed encouraging response rates when thalidomide was combined with temozolomide. However, the doses and schedules of temozolomide in those studies differed from the conventionally prescribed doses and schedules. It is not clear whether the improved response rates were attributable to the small number of patients in the studies, the different temozolomide doses and schedules, or the addition of thalidomide. Further phase iii studies are required to confirm whether a benefit is associated with the combination of temozolomide and thalidomide. Therefore, at this time, it is not recommended that thalidomide be combined with temozolomide.
Qualifying Statements
Dacarbazine is the only chemotherapy drug currently approved for the treatment of metastatic malignant melanoma. In large randomized trials, response rates with dacarbazine ranged from 6% to 15%. Almost all responses were partial, with a median response duration of only 7–8 months. Given these disappointing overall results, the consensus among most physicians who are treating patients with metastatic malignant melanoma is that recommending more convenient treatment or experimental treatment to these patients is appropriate.
Because of oral dosing, temozolomide is a reasonable choice, particularly for patients who would have difficulty traveling to cancer centres for intravenous chemotherapy.
Temozolomide has demonstrated efficacy equal to that of dacarbazine in a randomized phase iii trial. However, unlike dacarbazine, temozolomide is a convenient oral treatment that penetrates the blood–brain barrier and that has shown activity against brain metastases. Although surgery is the preferred treatment modality for patients with solitary brain metastases from melanoma, temozolomide is the preferred chemotherapy for patients with brain metastases who require systemic treatment.
PMCID: PMC1891190  PMID: 17576461
Melanoma; temozolomide; temodal; guideline report
13.  Bevacizumab in Combination With Radiotherapy and Temozolomide for Patients With Newly Diagnosed Glioblastoma Multiforme 
The Oncologist  2015;20(2):107-108.
Patients with a newly diagnosed glioblastoma multiforme (GBM) have a high risk of recurrent disease with a dismal outcome despite intensive treatment of sequential surgery and chemoradiotherapy with temozolomide (TMZ), followed by TMZ as a single agent. Bevacizumab (BV) may increase response rates to chemotherapy in the recurrent treatment setting of GBM. We hypothesized that a neoadjuvant treatment strategy for patients with newly diagnosed GBM using chemoradiotherapy plus BV would improve resectability and thus survival. We performed a phase II trial of the treatment strategy of BV plus chemoradiation to determine the safety of this combination in patients who had already undergone primary surgery for their GBM.
After a biopsy (6 patients) or a resection (13 patients) of a newly diagnosed GBM, 19 patients received radiotherapy (30 fractions of 2 Gy) in combination with daily TMZ 75 mg/m2 and BV 10 mg/kg on days 1, 14, and 28, followed by 6 monthly cycles of TMZ 150–200 mg/m2 on days 1–5.
The overall response rate was 26%. Three patients had a complete response after resection, and in two patients, a complete response after resection followed by chemoradiation plus BV was seen. No grade 3–4 toxicities were observed during combination treatment. The median progression-free survival was 9.6 months (95% confidence interval [CI]: 4.3–14.4 months). The median overall survival was 16 months (95% CI: 8.1–26.3 months), similar to a matched control group that received standard chemoradiotherapy from our institution.
Combination of bevacizumab with radiotherapy and TMZ is safe and feasible in patients with newly diagnosed GBM, but because of low response rates, this treatment strategy does not favor a neoadjuvant approach.
PMCID: PMC4319643  PMID: 25582142
14.  Randomized Phase II Trial of Chemoradiotherapy Followed by Either Dose-Dense or Metronomic Temozolomide for Newly Diagnosed Glioblastoma 
Journal of Clinical Oncology  2009;27(23):3861-3867.
Alternative dosing schedules of temozolomide may improve survival in patients with newly diagnosed glioblastoma (GBM) by increasing the therapeutic index, overcoming common mechanisms of temozolomide resistance, or both. The goal of this randomized phase II study was to evaluate two different temozolomide regimens in the adjuvant treatment of newly diagnosed GBM.
Patients and Methods
Adult patients with newly diagnosed GBM were randomly assigned to receive standard radiotherapy with concurrent daily temozolomide followed by six adjuvant cycles of either dose-dense (150 mg/m2 days 1 to 7 and 15 to 21) or metronomic (50 mg/m2 continuous daily) temozolomide. Maintenance doses of 13-cis-retinoic acid were then administered until tumor progression. The primary end point was overall survival (OS) at 1 year. Tumor tissue was assayed to determine O6-methylguanine–DNA methyltransferase (MGMT) promoter methylation status.
Eighty-five eligible patients were enrolled; 42 were randomly assigned to dose-dense and 43 to metronomic temozolomide. The 1-year survival rate was 80% for the dose-dense arm and 69% for the metronomic arm; median OS was 17.1 months (95% CI, 14.0 to 28.1 months) and 15.1 months (95% CI, 12.3 to 18.9 months), respectively. The most common toxicities were myelosuppression (leukopenia, neutropenia, and thrombocytopenia) and elevated liver enzymes. Pseudoprogression was observed in 37% of assessable patients and may have had an impact on estimates of progression-free survival (6.6 months in the dose-dense arm and 5.0 months in the metronomic arm).
Both dose-dense and metronomic temozolomide regimens were well tolerated with modest toxicity. The dose-dense regimen appears promising, with 1-year survival of 80%.
PMCID: PMC2727290  PMID: 19506159
15.  The History and Future of Chemotherapy for Melanoma 
Melanoma is considered a chemotherapy-resistant tumor, but in fact several chemotherapeutic agents show single-agent activity at the level of 10% to 15%, similar to the efficacy of the chemotherapeutic armamentarium used against other tumor types. Several combination chemotherapy regimens have been tested, but no survival benefit has been demonstrated. Few of these trials have been compared with standard dacarbazine (DTIC) in an adequately powered randomized trial, and even the largest of these trials were only powered to detect unrealistically large improvements in overall survival. In this article, the authors review past chemotherapy trials and the current state of chemotherapy for melanoma. Looking to the future, the authors are encouraged by recent observations that the addition of sorafenib to DTIC (or temozolomide) can increase response rates and survival. The authors suggest that this could form the core on which additional active chemotherapeutic drugs could be added with the hope of developing a regimen that improves overall survival. This paradigm of stepwise addition of active chemotherapeutic drugs has been successful in the development of chemotherapy regimens that improve survival in other solid tumor systems. In colon carcinoma, for example, the current regimens were built on fluorouracil (5FU)/leucovorin, which has similar activity to DTIC in melanoma. This could serve as a model for studies on melanoma.
PMCID: PMC3904102  PMID: 19464604
Dacarbazine; Temozolomide; Cisplatin; Sorafenib; Combination chemotherapy
16.  HMGB1 Mediates Endogenous TLR2 Activation and Brain Tumor Regression 
PLoS Medicine  2009;6(1):e1000010.
Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor that carries a 5-y survival rate of 5%. Attempts at eliciting a clinically relevant anti-GBM immune response in brain tumor patients have met with limited success, which is due to brain immune privilege, tumor immune evasion, and a paucity of dendritic cells (DCs) within the central nervous system. Herein we uncovered a novel pathway for the activation of an effective anti-GBM immune response mediated by high-mobility-group box 1 (HMGB1), an alarmin protein released from dying tumor cells, which acts as an endogenous ligand for Toll-like receptor 2 (TLR2) signaling on bone marrow-derived GBM-infiltrating DCs.
Methods and Findings
Using a combined immunotherapy/conditional cytotoxic approach that utilizes adenoviral vectors (Ad) expressing Fms-like tyrosine kinase 3 ligand (Flt3L) and thymidine kinase (TK) delivered into the tumor mass, we demonstrated that CD4+ and CD8+ T cells were required for tumor regression and immunological memory. Increased numbers of bone marrow-derived, tumor-infiltrating myeloid DCs (mDCs) were observed in response to the therapy. Infiltration of mDCs into the GBM, clonal expansion of antitumor T cells, and induction of an effective anti-GBM immune response were TLR2 dependent. We then proceeded to identify the endogenous ligand responsible for TLR2 signaling on tumor-infiltrating mDCs. We demonstrated that HMGB1 was released from dying tumor cells, in response to Ad-TK (+ gancyclovir [GCV]) treatment. Increased levels of HMGB1 were also detected in the serum of tumor-bearing Ad-Flt3L/Ad-TK (+GCV)-treated mice. Specific activation of TLR2 signaling was induced by supernatants from Ad-TK (+GCV)-treated GBM cells; this activation was blocked by glycyrrhizin (a specific HMGB1 inhibitor) or with antibodies to HMGB1. HMGB1 was also released from melanoma, small cell lung carcinoma, and glioma cells treated with radiation or temozolomide. Administration of either glycyrrhizin or anti-HMGB1 immunoglobulins to tumor-bearing Ad-Flt3L and Ad-TK treated mice, abolished therapeutic efficacy, highlighting the critical role played by HMGB1-mediated TLR2 signaling to elicit tumor regression. Therapeutic efficacy of Ad-Flt3L and Ad-TK (+GCV) treatment was demonstrated in a second glioma model and in an intracranial melanoma model with concomitant increases in the levels of circulating HMGB1.
Our data provide evidence for the molecular and cellular mechanisms that support the rationale for the clinical implementation of antibrain cancer immunotherapies in combination with tumor killing approaches in order to elicit effective antitumor immune responses, and thus, will impact clinical neuro-oncology practice.
Maria Castro and colleagues use cell line and transgenic mouse approaches to study the mechanisms underlying the immune response to glioblastoma multiforme.
Editors' Summary
Every year, more than 175,000 people develop a primary brain tumor (a cancer that starts in the brain rather than spreading in from elsewhere). Like all cancers, brain tumors develop when a cell acquires genetic changes that allow it to grow uncontrollably and that change other aspects of its behavior, including the proteins it makes. There are many different types of cells in the brain and, as a result, there are many different types of brain tumors. However, one in five primary brain tumors is glioblastoma multiforme (GBM; also known as grade 4 astrocytoma), a particularly aggressive cancer. With GBM, the average time from diagnosis to death is one year and only one person in 20 survives for five years after a diagnosis of GBM. Symptoms of GBM include headaches, seizures, and changes in memory, mood, or mental capacity. Treatments for GBM, which include surgery, radiotherapy, and chemotherapy, do not “cure” the tumor but they can ease these symptoms.
Why Was This Study Done?
Better treatments for GBM are badly needed, and one avenue that is being explored is immunotherapy—a treatment in which the immune system is used to fight the cancer. Because many tumors make unusual proteins, the immune system can sometimes be encouraged to recognize tumor cells as foreign invaders and kill them. Unfortunately, attempts to induce a clinically useful anti-GBM immune response have been unsuccessful, partly because the brain contains very few dendritic cells, a type of immune system cell that kick-starts effective immune responses by presenting foreign proteins to other immune system cells. Another barrier to immunotherapy for GBM is immune evasion by the tumor. Many tumors develop ways to avoid the immune response as they grow. For example, they sometimes reduce the expression of proteins that the immune system might recognize as foreign. In this study, the researchers test a new combined treatment strategy for GBM in which dendritic cells are encouraged to enter the brain and tumor cells are killed to release proteins capable of stimulating an effective antitumor immune response.
What Did the Researchers Do and Find?
The researchers first established brain tumors in mice. Then, they injected harmless viruses carrying the genes for Fms-like tyrosine kinase 3 ligand (Ftl3L; a protein that attracts dendritic cells) and for thymidine kinase (TK; cells expressing TK are killed by a drug called gancyclovir) into the tumor. Expression of both Flt3L and TK (but not of either protein alone) plus gancyclovir treatment shrank the tumors and greatly improved the survival of the mice. The researchers show that their strategy increased the migration of dendritic cells into the tumor provided they expressed an immune system protein called Toll-like receptor 2 (TLR2). TLR2 expression on the dendritic cells was also needed for an effective anti-tumor immune response and for tumor regression. TLR2 normally activates dendritic cells by binding to specific proteins on invading pathogens, so what was TLR2 binding to in the mouse tumors? The researchers reveal that TLR2 was responding to high-mobility-group box 1 (HMGB1), a protein released by the dying tumor cells by showing that treatment of the tumor-bearing mice with the HMGB1 inhibitor glycyrrhizin blocked the therapeutic effect of Flt3L/TK expression. Finally, the researchers report that other tumor cell types release HMGB1 when they are killed and that the Flt3L/TK expression strategy can also kill other tumors growing in mouse brains.
What Do These Findings Mean?
Results obtained in mouse models of human diseases do not always lead to effective treatments for human patients. Nevertheless, the findings of this study provide new insights into how an effective immune response against brain tumors might be brought about. Most importantly, they show that an effective strategy might need to both attract dendritic cells into the brain tumor and to kill tumor cells, so they release proteins that can activate the dendritic cells. That is, the authors suggest it's important to combine immunotherapies with tumor-killing strategies to provide effective treatments for primary and metastatic brain tumors
Additional Information.
Please access these Web sites via the online version of this summary at
The US National Cancer Institute provides information about brain tumors for patients and health professionals and about the the immune system and how it can be harnessed to fight cancer (in English and Spanish)
Cancer Research UK provides information on all aspects of brain tumors for patients and their caregivers
MedlinePlus provides links to further information about brain cancer, (including some links to information in Spanish)
The American Brain Tumor Association provides brain tumor resources and information
The National Brain Tumor Society provides educational and support services regarding brain tumors
PMCID: PMC2621261  PMID: 19143470
17.  Phase II and pharmacogenomics study of enzastaurin plus temozolomide during and following radiation therapy in patients with newly diagnosed glioblastoma multiforme and gliosarcoma 
Neuro-Oncology  2011;13(12):1331-1338.
This open-label, single-arm, phase II study combined enzastaurin with temozolomide plus radiation therapy (RT) to treat glioblastoma multiforme (GBM) and gliosarcoma. Adults with newly diagnosed disease and Karnofsky performance status (KPS) ≥ 60 were enrolled. Treatment was started within 5 weeks after surgical diagnosis. RT consisted of 60 Gy over 6 weeks. Temozolomide was given at 75 mg/m2 daily during RT and then adjuvantly at 200 mg/m2 daily for 5 days, followed by a 23-day break. Enzastaurin was given once daily during RT and in the adjuvant period at 250 mg/day. Cycles were 28 days. The primary end point was overall survival (OS). Progression-free survival (PFS), toxicity, and correlations between efficacy and molecular markers analyzed from tumor tissue samples were also evaluated. A prospectively planned analysis compared OS and PFS of the current trial with outcomes from 3 historical phase II trials that combined novel agents with temozolomide plus RT in patients with GBM or gliosarcoma. Sixty-six patients were enrolled. The treatment regimen was well tolerated. OS (median, 74 weeks) and PFS (median, 36 weeks) results from the current trial were comparable to those from a prior phase II study using erlotininb and were significantly better than those from 2 other previous studies that used thalidomide or cis-retinoic acid, all in combination with temozolomide plus RT. A positive correlation between O-6-methylguanine-DNA methyltransferase promoter methylation and OS was observed. Adjusting for age and KPS, no other biomarker was associated with survival outcome. Correlation of relevant biomarkers with OS may be useful in future trials.
PMCID: PMC3223090  PMID: 21896554
adjuvant therapy; enzastaurin; glioblastoma multiforme; radiation therapy; temozolomide
18.  The butterfly effect on glioblastoma: is volumetric extent of resection more effective than biopsy for these tumors? 
Journal of neuro-oncology  2014;120(3):625-634.
A subset of patients with glioblastoma (GBM) have butterfly GBM (bGBM) that involve both cerebral hemispheres by crossing the corpus callosum. The prognoses, as well as the effectiveness of surgery and adjuvant therapy, are unclear because studies are few and limited. The goals of this study were to: (1) determine if bGBM have worse outcomes than patients with non-bGBM, (2) determine if surgery is more effective than biopsy, and (3) identify factors independently associated with improved outcomes for these patients. Adult patients who underwent surgery for a newly diagnosed primary GBM at an academic tertiary-care institution between 2007 and 2012 were retrospectively reviewed and tumors were volumetrically measured. Of the 336 patients with newly diagnosed GBM who were operated on, 48 (14 %) presented with bGBM, where 29 (60 %) and 19 (40 %) underwent surgical resection and biopsy, respectively. In multivariate analysis, a bGBM was independently associated with poorer survival [HR (95 % CI) 1.848 (1.250–2.685), p < 0.003]. In matched- pair analysis, patients who underwent surgical resection had improved median survival than biopsy patients (7.0 vs. 3.5 months, p = 0.03). In multivariate analysis, increasing percent resection [HR (95 % CI) 0.987 (0.977–0.997), p = 0.01], radiation [HR (95 % CI) 0.431 (0.225–0.812), p = 0.009], and temozolomide [HR (95 % CI) 0.413 (0.212–0. 784), p = 0.007] were each independently associated with prolonged survival among patients with bGBM. This present study shows that while patients with bGBM have poorer prognoses compared to non-bGBM, these patients can also benefit from aggressive treatments including debulking surgery, maximal safe surgical resection, temozolomide chemotherapy, and radiation therapy.
PMCID: PMC4313925  PMID: 25193022
Butterfly; Corpus callosum; GBM; Glioblastoma; Radiation; Survival; Temozolomide
19.  Hypofractionated Radiotherapy and Stereotactic Boost with Concurrent and Adjuvant Temozolamide for Glioblastoma in Good Performance Status Elderly Patients – Early Results of a Phase II Trial 
Frontiers in Oncology  2012;2:122.
Glioblastoma Multiforme (GBM) is an aggressive primary brain neoplasm with dismal prognosis. Based on successful phase III trials, 60 Gy involved-field radiotherapy in 30 fractions over 6 weeks [Standard radiation therapy (RT)] with concurrent and adjuvant temozolomide is currently the standard of care. In this disease, age and Karnofsky Performance Status (KPS) are the most important prognostic factors. For elderly patients, clinical trials comparing standard RT with radiotherapy abbreviated to 40 Gy in 15 fractions over 3 weeks demonstrated similar outcomes, indicating shortened radiotherapy may be an appropriate option for elderly patients. However, these trials did not include temozolomide chemotherapy, and included patients with poor KPS, possibly obscuring benefits of more aggressive treatment for some elderly patients. We conducted a prospective Phase II trial to examine the efficacy of a hypofractionated radiation course followed by a stereotactic boost with concurrent and adjuvant temozolomide chemotherapy in elderly patients with good performance status. In this study, patients 65 years and older with a KPS > 70 and histologically confirmed GBM received 40 Gy in 15 fractions with 3D conformal technique followed by a 1–3 fraction stereotactic boost to the enhancing tumor. All patients also received concurrent and adjuvant temozolomide. Patients were evaluated 1 month post-treatment and every 2 months thereafter. Between 2007 and 2010, 20 patients (9 males and 11 females) were enrolled in this study. The median age was 75.4 years (range 65–87 years). At a median follow-up of 11 months (range 7–32 months), 12 patients progressed and 5 are alive. The median progression free survival was 11 months and the median overall survival was 13 months. There was no additional toxicity. These results indicate that elderly patients with good KPS can achieve outcomes comparable to the current standard of care using an abbreviated radiotherapy course, radiosurgery boost, and temozolomide.
PMCID: PMC3472503  PMID: 23087896
glioblastoma; stereotactic radiation; temozolamide
20.  Temozolomide in malignant glioma 
OncoTargets and therapy  2010;3:139-146.
Glioblastoma multiforme WHO grade IV (GBM) is the most aggressive malignant glioma and the most frequent primary tumor of the central nervous system. The median survival of newly diagnosed GBM patients was between 9 to 12 months prior to treatment with temozolomide being introduced. Primary resection that is as complete as possible is recommended for malignant glioma. Conventional fractionated irradiation 55 to 60 gy with concomitant temozolomide followed by standard temozolomide 6 cycles (5/28) (EORTC/NCIC-regime published by R Stupp in 2005) is the standard of care for newly diagnosed GBM after surgery, independent of the methylation status of the MGM-T gene promoter. Age is no contraindication for treatment with temozolomide, although comorbidity and performance status have to be considered. For temozolomide naive GBM and astrocytoma grade III patients with disease progression, temozolomide is still the treatment of choice outside of clinical studies. A general consensus regarding the schedule of choice has not yet been achieved; so far the 5 out of 28 days regimen (5/28) is the standard of care in most countries. Patients with disease progression after standard temozolomide (5/28) are candidates for clinical studies. Outside of clinical studies, dose-dense (7/7), prolonged (21/28), or metronomic (28/28) temozolomide, or alternatively a nitrosourea-based regimen can be an option. The excellent toxicity profile of temozolomide allows for various combinations with antitumor agents. None of these combinations, however, have been demonstrated to be statistically significantly superior compared to temozolomide alone. The role of lower dosed, dose-dense, or continuous regimen with or without drug combination and the role of temozolomide for newly diagnosed astrocytoma grade III and low grade glioma still has to be determined.
PMCID: PMC2939767  PMID: 20856849
glioblastoma multiforme; astrocytoma WHO grade III; malignant glioma; temozolomide
21.  Effective sensitization of temozolomide by ABT-888 is lost with development of TMZ resistance in glioblastoma xenograft lines 
Molecular cancer therapeutics  2009;8(2):407-414.
Resistance to temozolomide (TMZ) and radiotherapy (RT) is a major problem for patients with GBM but may be overcome using the PARP-inhibitor ABT-888. Using two primary GBM xenografts, the efficacy of ABT-888 combined with RT and/or TMZ was evaluated. Treatment with ABT-888 combined with TMZ resulted in significant survival prolongation (GBM12: 55.1%, p=0.005; GBM22: 54.4%, p=0.043). ABT-888 had no effect with RT alone, but significantly enhanced survival in GBM12 when combined with concurrent RT/TMZ. With multi-cycle therapy, ABT-888 further extended the survival benefit of TMZ in the inherently sensitive GBM12 and GBM22 xenograft lines. However, after in vivo selection for TMZ resistance, the derivative GBM12TMZ and GBM22TMZ lines were no longer sensitized by ABT-888 in combination with TMZ, and a similar lack of efficacy was observed in two other TMZ resistant tumor lines. Thus, the sensitizing effects of ABT-888 were limited to tumor lines that had not been previously exposed to TMZ, and these results suggest that patients with newly diagnosed GBM may be more likely to respond to combined TMZ/PARP inhibitor therapy than patients with recurrent disease.
PMCID: PMC2692390  PMID: 19174557
PARP; ABT-888; temozolomide; radiotherapy; glioblastoma
22.  Phase II study of irinotecan (CPT-11) in children with high-risk malignant brain tumors: the Duke experience. 
Neuro-Oncology  2002;4(2):102-108.
A phase II study of irinotecan (CPT-11) was conducted at Duke University Medical Center, Durham, NC, to evaluate the activity of this agent in children with high-risk malignant brain tumors. A total of 22 children were enrolled in this study, including 13 with histologically verified recurrent malignant brain tumors (glioblastoma multiforme [GBM] 4, anaplastic astrocytoma 1, ependymoma 5, and medulloblastoma/primitive neuroectodermal tumor 3), 5 with recurrent diffuse pontine glioma, and 4 with newly diagnosed GBM. All patients with recurrent tumor had prior chemotherapy and/or irradiation. Each course of CPT-11 consisted of 125 mg/m ( 2 ) per week given i.v. for 4 weeks followed by a 2-week rest period. Patients with recurrent tumors received therapy until disease progression or unacceptable toxicity. Patients with newly diagnosed tumors initially received 3 cycles of treatment to assess tumor response and then were allowed radiotherapy at physician's choice; patients who demonstrated a response to CPT-11 prior to radiotherapy were allowed to continue the drug after radiation until disease progression or unacceptable toxicity. A 25% to 50% dose reduction was made for grade III-IV toxicity. Responses were assessed after every course by gadolinium-enhanced MRI of the brain and spine. Twenty-two patients received a median of 2 courses of CPT-11 (range, 1-16). Responses were seen in 4 of 9 patients with GBM or anaplastic astrocytoma (44%; 95% confidence interval, 11%-82%) (complete response in 2 patients with recurrent GBM lasting 9 months and 48+ months; partial response in one patient with a newly diagnosed midbrain GBM lasting 18 months prior to radiotherapy; and partial response lasting 11 months in 1 patient with recurrent anaplastic astrocytoma), 1 of 5 patients with recurrent ependymoma (partial response initially followed by stable disease lasting 11 months), and none of 5 patients with recurrent diffuse pontine glioma. Two of 3 patients with medulloblastoma/primitive neuroectodermal tumor had stable disease for 9 and 13 months. Toxicity was mainly myelosuppression, with 12 of 22 patients (50%) suffering grade II-IV neutropenia. Seven patients required dose reduction secondary to neutropenia. CPT-11, given in this schedule, appears to be active in children with malignant glioma, medulloblastoma, and ependymoma with acceptable toxicity. Ongoing studies will demonstrate if activity of CPT-11 can be enhanced when combined with alkylating agents, including carmustine and temozolomide.
PMCID: PMC1920653  PMID: 11916501
23.  The DNA repair protein ALKBH2 mediates temozolomide resistance in human glioblastoma cells 
Neuro-Oncology  2012;15(3):269-278.
Glioblastoma multiforme (GBM; World Health Organization astrocytoma grade IV) is the most frequent and most malignant primary brain tumor in adults. Despite multimodal therapy, all such tumors practically recur during the course of therapy, causing a median survival of only 14.6 months in patients with newly diagnosed GBM. The present study was aimed at examining the expression of the DNA repair protein AlkB homolog 2 (ALKBH2) in human GBM and determining whether it could promote resistance to temozolomide chemotherapy.
ALKBH2 expression in GBM cell lines and in human GBM was determined by quantitative real-time PCR (qRT-PCR) and gene expression analysis, respectively. Drug sensitivity was assessed in GBM cells overexpressing ALKBH2 and in cells in which ALKBH2 expression was silenced by small-interfering (si)RNA. ALKBH2 expression following activation of the p53 pathway was examined by western blotting and qRT-PCR.
ALKBH2 was abundantly expressed in established GBM cell lines and human GBM, and temozolomide exposure increased cellular ALKBH2 expression levels. Overexpression of ALKBH2 in the U87 and U251 GBM cell lines enhanced resistance to the methylating agents temozolomide and methyl methanesulfonate but not to the nonmethylating agent doxorubicin. Conversely, siRNA-mediated knockdown of ALKBH2 increased sensitivity of GBM cells to temozolomide and methyl methanesulfonate but not to doxorubicin or cisplatin. Nongenotoxic activation of the p53 pathway by the selective murine double minute 2 antagonist nutlin-3 caused a significant decrease in cellular ALKBH2 transcription levels.
Our findings identify ALKBH2 as a novel mediator of temozolomide resistance in human GBM cells. Furthermore, we place ALKBH2 into a new cellular context by showing its regulation by the p53 pathway.
PMCID: PMC3578482  PMID: 23258843
DNA repair; glioblastoma; ALKBH2; p53; temozolomide
24.  The Added Value of Concurrently-Administered Temozolomide Versus Adjuvant Temozolomide Alone in Newly-Diagnosed Glioblastoma 
Journal of neuro-oncology  2008;88(1):43-50.
Temozolomide (TMZ), given concurrently with radiotherapy (RT) and as adjuvant monotherapy afterwards, has led to improved survival in glioblastoma multiforme (GBM). However, it is unclear whether its primary mechanism of action is through enhancement of radiation response or through independent cytotoxicity. We sought to determine the relative contribution of concomitant temozolomide in patients treated by concurrent and adjuvant TMZ versus adjuvant TMZ alone in the setting of newly-diagnosed GBM.
Patients and Methods
We identified patients diagnosed with GBM and treated with surgery, involved-field radiotherapy, and chemotherapy at MGH between January 1, 2002 and December 31, 2004. Eligible patients received either adjuvant temozolomide (group 1) alone or temozolomide concurrently with RT followed by adjuvant TMZ (group 2). The primary endpoint of this retrospective analysis is overall survival (OS), and the secondary endpoint is progression-free survival (PFS).
Forty-three patients (group 1, n=21; group 2, n=22) were included in this study. The median follow-up is 33.7 months for surviving patients. There were no significant differences in baseline characteristics (including age, KPS, resection status, and RPA class) between these two groups. Thrombocytopenia was more pronounced in group 1 (p=0.0407), but there were no other significant differences in toxicity. On univariate analysis, patients who received concurrent and adjuvant temozolomide (Group 2) experienced a 2-year OS of 51% and a median survival of 25.5 months, compared with a 2-year OS of 36% and a median survival of 15.6 months for Group 1 patients. This difference was statistically significant (log-rank p=0.0495). On multivariable analysis, the hazard ratio (HR) favoring concurrent TMZ trended towards significance (HR = 0.508, p=0.0839) despite modest patient numbers. There was no statistically significant difference in PFS.
Concurrent and adjuvant TMZ is associated with improved survival compared to adjuvant TMZ alone. These results highlight the potentiation of radiation effect by temozolomide in the clinical setting.
PMCID: PMC2658810  PMID: 18231723
25.  Patterns of care and survival for patients with glioblastoma multiforme diagnosed during 2006 
Neuro-Oncology  2012;14(3):351-359.
Standard treatment for glioblastoma multiforme (GBM) changed in 2005 when addition of temozolomide (TMZ) to maximal surgical resection followed by radiation therapy (RT) was shown to prolong survival in a clinical trial. In this study, we assessed treatment patterns and survival of patients with GBM in community settings in the United States. Patients with newly diagnosed GBM who were aged ≥20 years in 2006 (n = 1202) were identified as part of the National Cancer Institute 's Patterns of Care Studies. We assessed treatment patterns, and in the subset of patients who received total or partial surgical resection, we used multivariable regression analysis to assess patient, clinical, and health system factors associated with receipt of adjuvant chemotherapy and RT and survival through 2008. Approximately 65% of patients with GBM received total or partial surgical resection, and approximately 70% of these patients received adjuvant TMZ and RT. Receipt of adjuvant therapy was associated with patient age, marital status, health insurance, and tumor location. Median survival in all patients was 10 months (95% confidence interval [CI], 9–11 months). Receipt of adjuvant therapy following resection was associated with a lower risk of dying in adjusted analyses for patients who received TMZ and RT (hazard ratio [HR], 0.25; 95% CI, 0.18–0.35) and other adjuvant therapies (HR, 0.55; 95% CI, 0.37–0.81), compared with no adjuvant therapy. We observed rapid diffusion of a new standard of treatment, adjuvant and concurrent TMZ with RT, among adult patients with newly diagnosed GBM in the community setting following publication of a pivotal clinical trial.
PMCID: PMC3280803  PMID: 22241797
brain cancer; glioblastoma; practice patterns; SEER; temozolomide

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