Dynamics and predictors of hematologic toxicity during cranio-spinal irradiation.

Background: Craniospinal irradiation (CSI) is a complex radiotherapy (RT) technique required for treating specific brain tumors and some hematologic malignancies. With large volumes of hematogenous bone marrow (BM) being irradiated, CSI could cause acute hematologic toxicity, leading to treatment interruptions or severe complications. We report on the dynamics and dose/volume predictors of hematologic toxicity during CSI. Materials and methods: Pediatric patients (≤ 18years) undergoing CSI in a tertiary cancer center were included. Medical records were retrospectively reviewed for clinical data and blood parameters were collected at baseline and weekly, until four weeks after the end of RT. The BM substructures were contoured, and dose-volume parameters were extracted. We used Wilcoxon rank-sum test to compare quantitative data, Chi square test for qualitative data and receiver operating characteristics (ROC) curves for dose/volume thresholds. Results: Fifty-one patients were included. Severe toxicities (grade 3-4) were recorded as follows: 2% anemia, 8% thrombocytopenia, 25% leukopenia, 24% neutropenia. Ninety-eight percent of patients had lymphopenia (grade 1-4) at some point. Twenty-nine percent required granulocyte-colony stimulating factor, 50% had an infection and 8% required a blood transfusion. Dmean > 3.6 Gy and V15 Gy > 10.6% for Pelvic Bones were associated with a higher risk of developing any ≥ G3 toxicities. Dmean > 30-35 Gy to the thoracic and lumbar spine was predictive for G3-4 anemia and thrombocytopenia, and Cervical Spine Dmean > 30 Gy was associated with ≥ G3 neutropenia. Conclusion: CSI was well tolerated, without life-threatening complications in our cohort, but hematologic toxicity was frequent, with severity increasing with higher mean doses delivered to the hematogenous BM and larger volumes of BM receiving 30-35 Gy.

A Randomized Phase II Trial (TAMIGA) Evaluating the Efficacy and Safety of Continuous Bevacizumab Through Multiple Lines of Treatment for Recurrent Glioblastoma.

BACKGROUND: We assessed the efficacy and safety of bevacizumab (BEV) through multiple lines in patients with recurrent glioblastoma who had progressed after first-line treatment with radiotherapy, temozolomide, and BEV. PATIENTS AND METHODS: TAMIGA (NCT01860638) was a phase II, randomized, double-blind, placebo-controlled, multicenter trial in adult patients with glioblastoma. Following surgery, patients with newly diagnosed glioblastoma received first-line treatment consisting of radiotherapy plus temozolomide and BEV, followed by six cycles of temozolomide and BEV, then BEV monotherapy until disease progression (PD1). Randomization occurred at PD1 (second line), and patients received lomustine (CCNU) plus BEV (CCNU + BEV) or CCNU plus placebo (CCNU + placebo) until further disease progression (PD2). At PD2 (third line), patients continued BEV or placebo with chemotherapy (investigator's choice). The primary endpoint was survival from randomization. Secondary endpoints were progression-free survival in the second and third lines (PFS2 and PFS3) and safety. RESULTS: Of the 296 patients enrolled, 123 were randomized at PD1 (CCNU + BEV, n = 61; CCNU + placebo, n = 62). The study was terminated prematurely because of the high drop-out rate during first-line treatment, implying underpowered inferential testing. The proportion of patients receiving corticosteroids at randomization was similar (BEV 33%, placebo 31%). For the CCNU + BEV and CCNU + placebo groups, respectively, median survival from randomization was 6.4 versus 5.5 months (stratified hazard ratio [HR], 1.04; 95% confidence interval [CI], 0.69-1.59), median PFS2 was 2.3 versus 1.8 months (stratified HR, 0.70; 95% CI, 0.48-1.00), median PFS3 was 2.0 versus 2.2 months (stratified HR, 0.70; 95% CI, 0.37-1.33), and median time from randomization to a deterioration in health-related quality of life was 1.4 versus 1.3 months (stratified HR, 0.76; 95% CI, 0.52-1.12). The incidence of treatment-related grade 3 to 4 adverse events was 19% (CCNU + BEV) versus 15% (CCNU + placebo). CONCLUSION: There was no survival benefit and no detriment observed with continuing BEV through multiple lines in patients with recurrent glioblastoma. IMPLICATIONS FOR PRACTICE: Previous research suggested that there may be value in continuing bevacizumab (BEV) beyond progression through multiple lines of therapy. No survival benefit was observed with the use of BEV through multiple lines in patients with glioblastoma who had progressed after first-line treatment (radiotherapy + temozolomide + BEV). No new safety concerns arose from the use of BEV through multiple lines of therapy.

Bevacizumab plus radiotherapy-temozolomide for newly diagnosed glioblastoma.

BACKGROUND: Standard therapy for newly diagnosed glioblastoma is radiotherapy plus temozolomide. In this phase 3 study, we evaluated the effect of the addition of bevacizumab to radiotherapy-temozolomide for the treatment of newly diagnosed glioblastoma. METHODS: We randomly assigned patients with supratentorial glioblastoma to receive intravenous bevacizumab (10 mg per kilogram of body weight every 2 weeks) or placebo, plus radiotherapy (2 Gy 5 days a week; maximum, 60 Gy) and oral temozolomide (75 mg per square meter of body-surface area per day) for 6 weeks. After a 28-day treatment break, maintenance bevacizumab (10 mg per kilogram intravenously every 2 weeks) or placebo, plus temozolomide (150 to 200 mg per square meter per day for 5 days), was continued for six 4-week cycles, followed by bevacizumab monotherapy (15 mg per kilogram intravenously every 3 weeks) or placebo until the disease progressed or unacceptable toxic effects developed. The coprimary end points were investigator-assessed progression-free survival and overall survival. RESULTS: A total of 458 patients were assigned to the bevacizumab group, and 463 patients to the placebo group. The median progression-free survival was longer in the bevacizumab group than in the placebo group (10.6 months vs. 6.2 months; stratified hazard ratio for progression or death, 0.64; 95% confidence interval [CI], 0.55 to 0.74; P<0.001). The benefit with respect to progression-free survival was observed across subgroups. Overall survival did not differ significantly between groups (stratified hazard ratio for death, 0.88; 95% CI, 0.76 to 1.02; P=0.10). The respective overall survival rates with bevacizumab and placebo were 72.4% and 66.3% at 1 year (P=0.049) and 33.9% and 30.1% at 2 years (P=0.24). Baseline health-related quality of life and performance status were maintained longer in the bevacizumab group, and the glucocorticoid requirement was lower. More patients in the bevacizumab group than in the placebo group had grade 3 or higher adverse events (66.8% vs. 51.3%) and grade 3 or higher adverse events often associated with bevacizumab (32.5% vs. 15.8%). CONCLUSIONS: The addition of bevacizumab to radiotherapy-temozolomide did not improve survival in patients with glioblastoma. Improved progression-free survival and maintenance of baseline quality of life and performance status were observed with bevacizumab; however, the rate of adverse events was higher with bevacizumab than with placebo. (Funded by F. Hoffmann-La Roche; ClinicalTrials.gov number, NCT00943826.).

Sensitizer drugs for the treatment of temozolomide-resistant glioblastoma.

PURPOSE: Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor. Despite maximal cytoreductive surgery followed by chemoradiotherapy the prognosis is still poor. Although surgery and radiotherapy may have reached maximal effectiveness, chemotherapy has the potential to improve survival. The aim of this study was to evaluate in vitro the antitumor efficacy of tamoxifen (TAM), raloxifen (RAL), pyrimethamine (PYR) and alphanizomenon flos-aquae (AFA) in combination with temozolomide (TMZ) plus ionizing radiation against cultured glioblastoma stem-like cells and primary glioblastoma cells , as possible way to increase the treatment options in patients with therapy-refractory GBM. METHODS: Stem-like tumor cells and glioblastoma cells isolated from two GBM biopsies were established by cell proliferation assays. TAM, RAL, PYR and AFA were added prior to TMZ and ionizing irradiation. RESULTS: All tested drugs enhanced the cytotoxic effect of TMZ and sensitized cancer cells to radiotherapy as demonstrated by MTT assay and different staining reagents (TMRE, Hoechst dye and Annexin V) used for monitoring of several events in apoptosis. CONCLUSION: The administration of certain selective estrogen receptor modulators (SERMs) (TAM and RAL), PYR and AFA before conventional postoperative chemo radiotherapy for glioblastoma might increase therapy efficiency compared to standard oncological treatment. These results need to be extended in vivo on laboratory animals in order to test the encouraging results obtained in vitro.

Tomotherapy for cranio-spinal irradiation.

Tomotherapy is a method of delivering rotational IMRT offering various advantages, notably for complex and large targets such as the cranio-spinal axis. This systematic literature review reports on main clinical outcomes and toxicities in patients with various cancer types that received whole craniospinal axis irradiation (CSI) using Tomotherapy and offers a comprehensive comparison between Tomotherapy and other radiotherapy delivery techniques. Databases including PubMed, PubMed Central, Embase, and Cochrane were searched using the keywords "tomotherapy" AND "craniospinal". Fifty-six papers were included in the review. Patient population was adult in 9 papers, paediatric in 26 papers and mixed in 14 papers. Patients treated with helical Tomotherapy had similar disease-specific clinical outcomes and toxicities as patients treated using other techniques. Compared to any other technique, Tomotherapy provides better target coverage, homogeneity, and conformity in 23, 34 and 22 reports. Tomotherapy showed better organ-at-risk sparing for the thyroid, parotids, cochlea, eyes, heart and esophagus. Beam-On-Time (BOT) was reported to be longer for Tomotherapy in most studies (Median BOT: HT = 11 min, VMAT = 5.49 min, 3DCRT = 1.46 min). In conclusion, Tomotherapy offers good cranio-spinal axis coverage with improved homogeneity and conformity compared to other techniques, but with a considerably longer treatment time. Clinical outcome and toxicities suggest using Tomotherapy for CSI is efficient and safe.

Deep-learning magnetic resonance imaging-based automatic segmentation for organs-at-risk in the brain: Accuracy and impact on dose distribution.

Background and purpose: Normal tissue sparing in radiotherapy relies on proper delineation. While manual contouring is time consuming and subject to inter-observer variability, auto-contouring could optimize workflows and harmonize practice. We assessed the accuracy of a commercial, deep-learning, MRI-based tool for brain organs-at-risk delineation. Materials and methods: Thirty adult brain tumor patients were retrospectively manually recontoured. Two additional structure sets were obtained: AI (artificial intelligence) and AIedit (manually corrected auto-contours). For 15 selected cases, identical plans were optimized for each structure set. We used Dice Similarity Coefficient (DSC) and mean surface-distance (MSD) for geometric comparison and gamma analysis and dose-volume-histogram comparison for dose metrics evaluation. Wilcoxon signed-ranks test was used for paired data, Spearman coefficient(ρ) for correlations and Bland-Altman plots to assess level of agreement. Results: Auto-contouring was significantly faster than manual (1.1/20 min, p < 0.01). Median DSC and MSD were 0.7/0.9 mm for AI and 0.8/0.5 mm for AIedit. DSC was significantly correlated with structure size (ρ = 0.76, p < 0.01), with higher DSC for large structures. Median gamma pass rate was 74% (71-81%) for Plan_AI and 82% (75-86%) for Plan_AIedit, with no correlation with DSC or MSD. Differences between Dmean_AI and Dmean_Ref were ≤ 0.2 Gy (p < 0.05). The dose difference was moderately correlated with DSC. Bland Altman plot showed minimal discrepancy (0.1/0) between AI and reference Dmean/Dmax. Conclusions: The AI-model showed good accuracy for large structures, but developments are required for smaller ones. Auto-segmentation was significantly faster, with minor differences in dose distribution caused by geometric variations.

Randomized Phase II Study of Duligotuzumab (MEHD7945A) vs. Cetuximab in Squamous Cell Carcinoma of the Head and Neck (MEHGAN Study).

BACKGROUND: Duligotuzumab, a novel dual-action humanized IgG1 antibody that blocks ligand binding to epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 3 (HER3), inhibits signaling from all ligand-dependent HER dimers, and can elicit antibody-dependent cell-mediated cytotoxicity. High tumor-expression of neuregulin 1 (NRG1), a ligand to HER3, may enhance sensitivity to duligotuzumab. METHODS: This multicenter, open-label, randomized phase II study (MEHGAN) evaluated drug efficacy in patients with recurrent/metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) progressive on/after chemotherapy and among patients with NRG1-high tumors. Patients received duligotuzumab (1100 mg IV, q2w) or cetuximab (400 mg/m2 load, 250 mg/m2 IV, q1w) until progression or intolerable toxicity. Tumor samples were assayed for biomarkers [NRG1, ERBB3, and human papillomavirus (HPV) status]. RESULTS: Patients (N = 121) were randomized (duligotuzumab:cetuximab; 59:62), median age 62 years; ECOG 0-2. Both arms (duligotuzumab vs. cetuximab, respectively) showed comparable progression-free survival [4.2 vs. 4.0 months; HR: 1.23 (90% confidence interval (CI): 0.89-1.70)], overall survival [7.2 vs. 8.7 months; HR 1.15 (90% CI: 0.81-1.63)], and objective response rate (12 vs. 14.5%), with no difference between patients with NRG1-high tumors or ERBB3-low tumors. Responses in both arms were confined to HPV-negative patients. Grade ≥3 adverse events (AEs) (duligotuzumab vs. cetuximab, respectively) included infections (22 vs. 11.5%) and GI disorders (17 vs. 7%), contributing to higher rates of serious AEs (41 vs. 29.5%). Metabolic disorders were less frequent with duligotuzumab (10 vs. 16%); any grade rash-related events were less with duligotuzumab (49 vs. 67%). CONCLUSION: While several lines of preclinical evidence had supported the premise that the blockade of HER3 in addition to that of EGFR may improve outcomes for patients with R/M SCCHN overall or specifically in those patients whose tumors express high levels of NRG1, this study provided definitive clinical evidence refuting this hypothesis. Duligotuzumab did not improve patient outcomes in comparison to cetuximab despite frequent expression of NRG1. These data indicate that inhibition of EGFR alone is sufficient to block EGFR-HER3 signaling, suggesting that HER2 plays a minimal role in this disease. Extensive biomarker analyses further show that HPV-negative SCCHN but not HPV-positive SCCHN are most likely to respond to EGFR blockage by cetuximab or duligotuzumab.