Edwin Lok

Dexamethasone exerts profound immunologic interference on treatment efficacy for recurrent glioblastoma

Background: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.Methods: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.Results: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.Conclusions: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.

Response assessment of novoTTF-100A versus best physician’s choice chemotherapy in recurrent glioblastoma.

The NovoTTF‐100A device emits frequency‐tuned alternating electric fields that interfere with tumor cell mitosis. In phase III trial for recurrent glioblastomas, NovoTTF‐100A was shown to have equivalent efficacy and less toxicity when compared to Best Physicians Choice (BPC) chemotherapy. We analyzed the characteristics of responders and nonresponders in both cohorts to determine the characteristics of response and potential predictive factors. Tumor response and progression were determined by Macdonald criteria. Time to response, response duration, progression‐free survival (PFS) ± Simon–Makuch correction, overall survival (OS), prognostic factors, and relative hazard rates were compared between responders and nonresponders. Median response duration was 7.3 versus 5.6 months for NovoTTF‐100A and BPC chemotherapy, respectively (P = 0.0009). Five of 14 NovoTTF‐100A responders but none of seven BPC responders had prior low‐grade histology. Mean cumulative dexamethasone dose was 35.9 mg for responders versus 485.6 mg for nonresponders in the NovoTTF‐100A cohort (P < 0.0001). Hazard analysis showed delayed tumor progression in responders compared to nonresponders. Simon–Makuch‐adjusted PFS was longer in responders than in nonresponders treated with NovoTTF‐100A (P = 0.0007) or BPC chemotherapy (P = 0.0222). Median OS was longer for responders than nonresponders treated with NovoTTF‐100A (P < 0.0001) and BPC chemotherapy (P = 0.0235). Pearson analysis showed strong correlation between response and OS in NovoTTF‐100A (P = 0.0002) but not in BPC cohort (P = 0.2900). Our results indicate that the response characteristics favor NovoTTF‐100A and data on prior low‐grade histology and dexamethasone suggest potential genetic and epigenetic determinants of NovoTTF‐100A response.

The natural history of intravascular lymphomatosis

Intravascular lymphomatosis (IVL) is a rare and clinically devastating form of extranodal B‐cell non‐Hodgkins lymphoma. We performed a comprehensive analysis of the literature on IVLs published between 1959 and 2011 and evaluated the natural history as well as identified prognostic and predictive factors in patients. Nonparametric two‐tailed Mann–Whitney U‐test and Mantel–Cox log rank test were used to evaluate the survival intervals and prognostic factors. Multivariate analysis of variance (MANOVA) and chi‐squared statistics were carried out to examine treatment‐related predictive factors. Of the 740 patients with IVL, 651 (88%) had a diagnosis of B‐cell lymphoma, 45 (6%) with T‐cell lymphoma, and 12 patients (2%) with NK cell lymphoma. Central nervous system (CNS) IVL had the highest proportion of postmortem diagnosis, 250 (60%) compared to 21 (8%) of skin, 28 (11%) of bone marrow (BM) and spleen, and 17 (7%) of lung IVLs. Age <70 years (P = 0.0073), non‐CNS site of initial diagnosis (P = 0.0014), lactate dehydrogenase (LDH) <700 (P = 0.0112), and rituximab treatment (P < 0.0001) were favorable prognostic factors. Gender, ethnicity, hemoglobin, BM biopsy, and the type of imaging studies used were not significant. Rituximab and doxorubicin treatment worked significantly better in patients with age >71 and LDH >577 compared to nonrituximab, nondoxorubicin regimens (MANOVA 2 degrees of freedom, P = 0.0345), with a median time from treatment to death of 20.0 (95% confidence interval [CI] 14.0–N/A, n = 14) months versus 2.0 (95%CI 0.5–N/A, n = 5) (χ2 = 4.7, P = 0.0304). Patients with CNS IVL relapsed primarily in the CNS (88%) while same‐organ relapse occurred less frequently in skin (23%), BM and spleen (50%) and lung (20%) IVLs. Our results indicate that IVL is primarily a disease of B‐lymphoma cells. Timely diagnosis and treatment with rituximab‐based chemotherapy improve patient survival. The pattern of recurrence is different between CNS IVL and IVLs in other organs.

An Overview of Alternating Electric Fields Therapy (NovoTTF Therapy) for the Treatment of Malignant Glioma

As with many cancer treatments, tumor treating fields (TTFields) target rapidly dividing tumor cells. During mitosis, TTFields-exposed cells exhibit uncontrolled membrane blebbing at the onset of anaphase, resulting in aberrant mitotic exit. Based on these criteria, at least two protein complexes have been proposed as TTFields’ molecular targets, including α/β-tubulin and the septin 2, 6, 7 heterotrimer. After aberrant mitotic exit, cells exhibited abnormal nuclei and signs of cellular stress, including decreased cellular proliferation and p53 dependence, and exhibit the hallmarks of immunogenic cell death, suggesting that TTFields treatment may induce an antitumor immune response. Clinical trials lead to Food and Drug Administration approval for their treatment of recurrent glioblastoma. Detailed modeling of TTFields within the brain suggests that the location of the tumor may affect treatment efficacy. These observations have a profound impact on the use of TTFields in the clinic, including what co-therapies may be best applied to boost its efficacy.

Tumor treating fields therapy device for glioblastoma: physics and clinical practice considerations.

Alternating electric fields therapy, as delivered by the tumor treating fields device, is a new modality of cancer treatment that has been approved by the US FDA for recurrent glioblastoma. At a frequency of 200 kHz, these fields emanate from transducer arrays on the surface of the patient’s scalp into the brain and perturb processes necessary for cytokinesis during tumor cell mitosis. In the registration Phase III trial for recurrent glioblastoma patients, the efficacy of the tumor treating fields as monotherapy was equivalent to chemotherapy, while scalp irritation was its major adverse event compared with systemic toxicities that were associated with cytotoxic chemotherapies. Alternating electric fields therapy is, therefore, an essential option for the treatment of recurrent glioblastoma. Here, we summarize our current knowledge of the physics, cell biology and clinical data supporting the use of the tumor treating fields therapy.

Computed modeling of alternating electric fields therapy for recurrent glioblastoma

Tumor treating fields (TTFields) are alternating electric fields frequency tuned to 200 kHz for the treatment of recurrent glioblastoma. We report a patient treated with TTFields and determined the distribution of TTFields intracranially by computerized simulation using co‐registered postgadolinium T1‐weighted, T2, and MP RAGE images together with pre‐specified conductivity and relative permittivity values for various cerebral structures. The distribution of the electric fields within the brain is inhomogeneous. Higher field intensities were aggregated near the ventricles, particularly at the frontal and occipital horns. The recurred tumor was found distant from the primary glioblastoma and it was located at a site of relatively lower electric field intensity. Future improvement in TTFields treatment may need to take into account the inhomogeneity of the electric field distribution within the brain.

Melanoma brain metastasis globally reconfigures chemokine and cytokine profiles in patient cerebrospinal fluid.

The aggressiveness of melanoma is believed to be correlated with tumor–stroma-associated immune cells. Cytokines and chemokines act to recruit and then modulate the activities of these cells, ultimately affecting disease progression. Because melanoma frequently metastasizes to the brain, we asked whether global differences in immunokine profiles could be detected in the cerebrospinal fluid (CSF) of melanoma patients and reveal aspects of tumor biology that correlate with patient outcomes. We therefore measured the levels of 12 cytokines and 12 chemokines in melanoma patient CSF and the resulting data were analyzed to develop unsupervised hierarchical clustergrams and heat maps. Unexpectedly, the overall profiles of immunokines found in these samples showed a generalized reconfiguration of their expression in melanoma patient CSF, resulting in the segregation of individuals with melanoma brain metastasis from nondisease controls. Chemokine CCL22 and cytokines IL1&agr;, IL4, and IL5 were reduced in most samples, whereas a subset including CXCL10, CCL4, CCL17, and IL8 showed increased expression. Further, analysis of clusters identified within the melanoma patient set comparing patient outcome suggests that suppression of IL1&agr;, IL4, IL5, and CCL22, with concomitant elevation of CXCL10, CCL4, and CCL17, may correlate with more aggressive development of brain metastasis. These results suggest that global immunokine suppression in the host, together with a selective increase in specific chemokines, constitute a predominant immunomodulatory feature of melanoma brain metastasis. These alterations likely drive the course of this disease in the brain and variations in the immune profiles of individual patients may predict outcomes.

Clinical benefit in recurrent glioblastoma from adjuvant NovoTTF-100A and TCCC after temozolomide and bevacizumab failure: a preliminary observation.

The NovoTTF‐100A is a device that emits alternating electric fields and it is approved for the treatment of recurrent glioblastoma. It works by perturbing tumor cells during mitosis as they enter anaphase leading to aneuploidy, asymmetric chromosome segregation and cell death with evidence of increased immunogenicity. Clinical trial data have shown equivalent efficacy when compared to salvage chemotherapies in recurrent disease. Responders were found to have had a lower dexamethasone usage and a higher rate of prior low‐grade histology. We treated a series of patients with NovoTTF‐100A and bevacizumab alone (n = 34) or in combination with a regimen consisting of 6‐thioguanine, lomustine, capecitabine, and celecoxib (TCCC) (n = 3). Compared to the former cohort, the latter cohort exhibited a trend for prolonged overall survival, median 4.1 (0.3–22.7) months versus 10.3 (7.7–13.6) months respectively (P = 0.0951), with one experiencing an objective response with a 50% reduction in tumor size on magnetic resonance imaging despite possessing a larger tumor size at baseline and more severe neurologic dysfunction than the median for either group. These observations illustrate the possibility of improving survival and achieving a response in patients with end‐stage recurrent glioblastoma by biasing the tumor toward anti‐tumor immunologic response with a combination of NovoTTF‐100A and TCCC, as well as the continuation of bevacizumab in order to limit dexamethasone use due to its global immunosuppressive effect on the patient.

Analysis of physical characteristics of Tumor Treating Fields for human glioblastoma

Tumor Treating Fields (TTFields) therapy is an approved treatment that has known clinical efficacy against recurrent and newly diagnosed glioblastoma. However, the distribution of the electric fields and the corresponding pattern of energy deposition in the brain are poorly understood. To evaluate the physical parameters that may influence TTFields, postacquisition MP‐RAGE, T1 and T2 MRI sequences from a responder with a right parietal glioblastoma were anatomically segmented and then solved using finite‐element method to determine the distribution of the electric fields and rate of energy deposition at the gross tumor volume (GTV) and other intracranial structures. Electric field–volume histograms (EVH) and specific absorption rate–volume histograms (SARVH) were constructed to numerically evaluate the relative and/or absolute magnitude volumetric differences between models. The electric field parameters EAUC, VE150, E95%, E50%, and E20%, as well as the SAR parameters SARAUC, VSAR7.5, SAR95%, SAR50%, and SAR20%, facilitated comparisons between models derived from various conditions. Specifically, TTFields at the GTV were influenced by the dielectric characteristics of the adjacent tissues as well as the GTV itself, particularly the presence or absence of a necrotic core. The thickness of the cerebrospinal fluid on the convexity of the brain and the geometry of the tumor were also relevant factors. Finally, the position of the arrays also influenced the electric field distribution and rate of energy deposition in the GTV. Using EVH and SARVH, a personalized approach for TTFields treatment can be developed when various patient‐related and tumor‐related factors are incorporated into the planning procedure.

Alternating Electric Fields Therapy for Malignant Gliomas: From Bench Observation to Clinical Reality

Alternating electric fields of intermediate frequencies, also known as Tumor Treating Fields (TTFields or TTF) is a novel anticancer treatment modality that disrupts tumor cell mitosis at the metaphase-anaphase transition, leading to mitotic catastrophe, aberrant mitotic exit, and/or cell death. It is realized through alteration of the cytokinetic cleavage furrow by interference of proteins possessing large dipole moments, like septin heterotrimer complex and α/β-tubulin, and that results in disordered membrane contraction and failed cytokinesis. Aberrant mitotic exit also elicits immunogenic cell death, which may potentiate an immune response against treated tumors. Notably, in patients with recurrent glioblastoma multiforme (GBM) a prospective clinical trial demonstrated comparable overall survival and progression-free survival after TTFields therapy and best physicians choice chemotherapy. Moreover, it was shown that in patients with newly diagnosed GBM initially treated with standard chemoradiotherapy with daily temozolomide (TMZ), adjuvant TTFields combined with TMZ offered better survival than adjuvant TMZ alone. Therefore, TTFields therapy can be appreciated as a standard treatment option in cases of intracranial malignant gliomas, whereas future studies should establish its optimal combination with other existing anticancer modalities, which may offer additional survival benefits for patients.