Treatment outcome of patients with recurrent glioblastoma multiforme:A retrospective multicenter analysis

Glioblastoma multiforme (GBM) universally recurs with dismal prognosis. We evaluated the efficacy of standard treatment strategies for patients with recurrent GBM (rGBM). From two centers in the Netherlands, 299 patients with rGBM after first-line treatment, diagnosed between 2005 and 2014, were retrospectively evaluated. Four different treatment strategies were defined: systemic treatment (SYST), re-irradiation (RT), re-resection followed by adjuvant treatment (SURG) and best supportive care (BSC). Median OS for all patients was 6.5 months, and median PFS (excluding patients receiving BSC) was 5.5 months. Older age, multifocal lesions and steroid use were significantly associated with a shorter survival. After correction for confounders, patients receiving SYST (34.8%) and SURG (18.7%) had a significantly longer survival than patients receiving BSC (39.5%), 7.3 and 11.0 versus 3.1 months, respectively [HR 0.46 (p &lt;0.001) and 0.36 (p &lt;0.001)]. Median survival for patients receiving RT (7.0%) was 9.2 months, but this was not significantly different from patients receiving BSC (p = 0.068). Patients receiving SURG compared to SYST had a longer PFS (9.0 vs. 4.3 months, respectively; p &lt;0.001), but no difference in OS was observed. After adjustments for confounders, patients with rGBM selected for treatment with SURG or SYST do survive significantly longer than patients who are selected for BSC based on clinical parameters. The value of reoperation versus systemic treatment strategies needs further investigation.</p

Individualized early death and long-term survival prediction after stereotactic radiosurgery for brain metastases of non-small cell lung cancer:Two externally validated nomograms

Introduction Commonly used clinical models for survival prediction after stereotactic radiosurgery (SRS) for brain metastases (BMs) are limited by the lack of individual risk scores and disproportionate prognostic groups. In this study, two nomograms were developed to overcome these limitations. Methods 495 patients with BMs of NSCLC treated with SRS for a limited number of BMs in four Dutch radiation oncology centers were identified and divided in a training cohort (n = 214, patients treated in one hospital) and an external validation cohort n = 281, patients treated in three other hospitals). Using the training cohort, nomograms were developed for prediction of early death (<3 months) and long-term survival (>12 months) with prognostic factors for survival. Accuracy of prediction was defined as the area under the curve (AUC) by receiver operating characteristics analysis for prediction of early death and long term survival. The accuracy of the nomograms was also tested in the external validation cohort. Results Prognostic factors for survival were: WHO performance status, presence of extracranial metastases, age, GTV largest BM, and gender. Number of brain metastases and primary tumor control were not prognostic factors for survival. In the external validation cohort, the nomogram predicted early death statistically significantly better (p < 0.05) than the unfavorable groups of the RPA, DS-GPA, GGS, SIR, and Rades 2015 (AUC = 0.70 versus range AUCs = 0.51–0.60 respectively). With an AUC of 0.67, the other nomogram predicted 1 year survival statistically significantly better (p < 0.05) than the favorable groups of four models (range AUCs = 0.57–0.61), except for the SIR (AUC = 0.64, p = 0.34). The models are available on www.predictcancer.org. Conclusion The nomograms predicted early death and long-term survival more accurately than commonly used prognostic scores after SRS for a limited number of BMs of NSCLC. Moreover these nomograms enable individualized probability assessment and are easy into use in routine clinical practice

An Essential Difference between the Flavonoids MonoHER and Quercetin in Their Interplay with the Endogenous Antioxidant Network

Antioxidants can scavenge highly reactive radicals. As a result the antioxidants are converted into oxidation products that might cause damage to vital cellular components. To prevent this damage, the human body possesses an intricate network of antioxidants that pass over the reactivity from one antioxidant to another in a controlled way. The aim of the present study was to investigate how the semi-synthetic flavonoid 7-mono-O-(β-hydroxyethyl)-rutoside (monoHER), a potential protective agent against doxorubicin-induced cardiotoxicity, fits into this antioxidant network. This position was compared with that of the well-known flavonoid quercetin. The present study shows that the oxidation products of both monoHER and quercetin are reactive towards thiol groups of both GSH and proteins. However, in human blood plasma, oxidized quercetin easily reacts with protein thiols, whereas oxidized monoHER does not react with plasma protein thiols. Our results indicate that this can be explained by the presence of ascorbate in plasma; ascorbate is able to reduce oxidized monoHER to the parent compound monoHER before oxidized monoHER can react with thiols. This is a major difference with oxidized quercetin that preferentially reacts with thiols rather than ascorbate. The difference in selectivity between monoHER and quercetin originates from an intrinsic difference in the chemical nature of their oxidation products, which was corroborated by molecular quantum chemical calculations. These findings point towards an essential difference between structurally closely related flavonoids in their interplay with the endogenous antioxidant network. The advantage of monoHER is that it can safely channel the reactivity of radicals into the antioxidant network where the reactivity is completely neutralized

Resectability and Ablatability Criteria for the Treatment of Liver Only Colorectal Metastases:Multidisciplinary Consensus Document from the COLLISION Trial Group

The guidelines for metastatic colorectal cancer crudely state that the best local treatment should be selected from a 'toolbox' of techniques according to patient- and treatment-related factors. We created an interdisciplinary, consensus-based algorithm with specific resectability and ablatability criteria for the treatment of colorectal liver metastases (CRLM). To pursue consensus, members of the multidisciplinary COLLISION and COLDFIRE trial expert panel employed the RAND appropriateness method (RAM). Statements regarding patient, disease, tumor and treatment characteristics were categorized as appropriate, equipoise or inappropriate. Patients with ECOG≤2, ASA≤3 and Charlson comorbidity index ≤8 should be considered fit for curative-intent local therapy. When easily resectable and/or ablatable (stage IVa), (neo)adjuvant systemic therapy is not indicated. When requiring major hepatectomy (stage IVb), neo-adjuvant systemic therapy is appropriate for early metachronous disease and to reduce procedural risk. To downstage patients (stage IVc), downsizing induction systemic therapy and/or future remnant augmentation is advised. Disease can only be deemed permanently unsuitable for local therapy if downstaging failed (stage IVd). Liver resection remains the gold standard. Thermal ablation is reserved for unresectable CRLM, deep-seated resectable CRLM and can be considered when patients are in poor health. Irreversible electroporation and stereotactic body radiotherapy can be considered for unresectable perihilar and perivascular CRLM 0-5cm. This consensus document provides per-patient and per-tumor resectability and ablatability criteria for the treatment of CRLM. These criteria are intended to aid tumor board discussions, improve consistency when designing prospective trials and advance intersociety communications. Areas where consensus is lacking warrant future comparative studies.</p

The role of biological dose-escalation for pancreatic cancer

The role of chemo-radiotherapy for treatment of locally advanced pancreatic cancer (LAPC) has been discussed for many years, and the absence of an overall survival benefit compared to gemcitabine chemotherapy alone in the recent LAP07 study seems to have increased the controversy. However, even in this study, chemo-radiotherapy resulted in decreased local progression (p = 0.03). In combination with increased efficacy of novel systemic therapy consisting of oxaliplatin, irinotecan, fluorouracil and leucovorin (FOLFIRINOX), radiation dose-escalation may show to be beneficial in LAPC. Stereotactic body radiation therapy (SBRT) can be expected to be the most suitable approach to perform local radiation dose-escalation, and has been shown to be both effective and tolerable at doses of 25–35 Gy in 3–5 fractions. Whether further dose-escalation for LAPC will be both feasible and useful is debatable, because of dose restrictions to adjacent critical organs at risk, and the observation that thus far a benefit of delivering BED10 in excess of 70 Gy has not shown to improve local control significantly. If an attempt to further dose-escalate is performed, stereotactic MR-guided adaptive radiation therapy (SMART) theoretically has the highest potential. In addition to superior soft-tissue setup without the need for implanted fiducial markers and online MR-guidance during delivery with minimal safety margins, daily plan adaptation directed at avoiding undue high doses to critical organs such as the duodenum, stomach and bowel are advantages of this technique over current SBRT. This paper aims to illustrate the SMART technique, which has been delivered in 300 fractions for LAPC or locally recurrent pancreatic cancer at Amsterdam UMC since early 2016

Whole brain radiotherapy versus stereotactic radiosurgery for 4-10 brain metastases:a phase III randomised multicentre trial

Background: Maintenance of quality of life is the primary goal during treatment of brain metastases (BM). This is a protocol of an ongoing phase III randomised multicentre study. This study aims to determine the exact additional palliative value of stereotactic radiosurgery (SRS) over whole brain radiotherapy (WBRT) in patients with 4-10 BM. Methods: The study will include patients with 4-10 BM from solid primary tumours diagnosed on a high-resolution contrast-enhanced MRI scan with a maximum lesional diameter of 2.5 cm in any direction and a maximum cumulative lesional volume of 30 cm3. Patients will be randomised between WBRT in five fractions of 4 Gy to a total dose of 20 Gy (standard arm) and single dose SRS to the BMs (study arm) in the range of 15-24 Gy. The largest BM or a localisation in the brainstem will determine the prescribed SRS dose. The primary endpoint is difference in quality of life (EQ5D EUROQOL score) at 3 months after radiotherapy with regard to baseline. Secondary endpoints are difference in quality of life (EQ5D EUROQOL questionnaire) at 6, 9 and 12 months after radiotherapy with regard to baseline. Other secondary endpoints are at 3, 6, 9 and 12 months after radiotherapy survival, Karnofsky ≥ 70, WHO performance status, steroid use (mg), toxicity according to CTCAE V4.0 including hair loss, fatigue, brain salvage during follow-up, type of salvage, time to salvage after randomisation and Barthel index. Facultative secondary endpoints are neurocognition with the Hopkins verbal learning test revised, quality of life EORTC QLQ-C30, quality of life EORTC BN20 brain module and fatigue scale EORTC QLQ-FA13. Discussion: Worldwide, most patients with more than 4 BM will be treated with WBRT. Considering the potential advantages of SRS over WBRT, i.e. limiting radiation doses to uninvolved brain and a high rate of local tumour control by just a single treatment with fewer side effects, such as hair loss and fatigue, compared to WBRT, SRS might be a suitable alternative for patients with 4-10 BM. Trial registration: Trial registration number: NCT02353000 , trial registration date 15th January 2015, open for accrual 1st July 2016, nine patients were enrolled in this trial on 14th April 2017

MR-guided Gated Stereotactic Radiation Therapy Delivery for Lung, Adrenal, and Pancreatic Tumors: A Geometric Analysis

PURPOSE: We implemented magnetic resonance-guided breath-hold stereotactic body radiation therapy in combination with visual feedback using the MRIdian system. Both accuracy of gated delivery and reproducibility of tumor positions were studied. METHODS AND MATERIALS: Tumor tracking is realized through repeated magnetic resonance imaging in a single sagittal plane at 4 frames per second with deformable image registration. An in-room monitor allowed visualization of the tracked gross tumor volume (GTV) contour and the planning target volume (PTV) (GTV + 3 mm), which was the gating boundary. For each delivery, a predefined threshold-region of interest percentage (ROI%) allows a percentage of GTV area to be outside the gating boundary before a beam-hold is triggered. Accuracy of gated delivery and tumor position reproducibility during breath-holds was analyzed for 15 patients (87 fractions) with lung, adrenal, and pancreas tumors. For each fraction, we analyzed (1) reproducibility of system-tracked GTV centroid position within the PTV; (2) geometric coverage of GTV area within the PTV; (3) treatment duty cycle efficiency; (4) effects of threshold ROI% settings on treatment duty cycle efficiency and GTV area coverage; and (5) beam-off latency effect on mean GTV coverage. RESULTS: For lung, adrenal, and pancreatic tumors, grouped 5th to 95th percentile distributions of GTV centroid positions in the dorsoventral direction, relative to PTV-center of mass (COM), were, respectively, -3.3 mm to 2.8 mm, -2.5 mm to 3.7 mm, and -4.4 mm to 2.9 mm. Corresponding distributions in the craniocaudal direction were -2.6 mm to 4.6 mm, -4.1 mm to 4.4 mm, and -4.4 mm to 4.5 mm, respectively. Mean GTV areas encompassed during beam-on for all fractions were 94.6%, 94.3%, and 95.3% for lung, adrenal, and pancreas tumors, respectively. Mean treatment duty cycle efficiency ranged from 67% to 87% for these tumors. Use of higher threshold-ROI% resulted in increased duty cycle efficiency, at the cost of a small decrease in GTV area coverage. The beam-off latency had a marginal impact on the GTV coverage. CONCLUSIONS: Gated stereotactic body radiation therapy delivery during breath-hold, real-time magnetic resonance guidance resulted in at least 95% geometric GTV coverage in lung, adrenal, and pancreatic tumors