A. Bruynzeel

The effect of monohydroxyethylrutoside on doxorubicin-induced cardiotoxicity in patients treated for metastatic cancer in a phase II study.

The purpose of this study was to investigate the cardioprotective effect of the semisynthetic flavonoid 7-monohydroxyethylrutoside (monoHER) on doxorubicin (DOX)-induced cardiotoxicity in a phase II study in patients with metastatic cancer. Eight patients with metastatic cancer were treated with DOX preceded by a 10 min i.v. infusion of 1500 mg m−2 monoHER. Five patients were examined by endomyocardial biopsy after reaching a cumulative dose of 300 mg m−2. Histopathological changes in the cardiomyocytes (Billingham score) were compared with those described in literature for patients treated with DOX only. The mean biopsy score of the patients was higher (2.7) than the mean score (1.4) of historical data of patients who received similar cumulative doses of DOX. Although there is a considerable variability in few investigated patients, it was indicative that monoHER enhanced DOX-induced cardiotoxicity. However, the antitumour activity of DOX seemed better than expected: three of the four patients with metastatic soft-tissue sarcoma had a partial remission and the fourth patient stable disease. It is likely that the relatively high dose of monoHER is responsible for the lack of cardioprotection and for the high response rate in patients with soft-tissue sarcoma possibly by depleting the glutathione defense system in both heart and tumour.

Anti-inflammatory agents and monoHER protect against DOX-induced cardiotoxicity and accumulation of CML in mice

Cardiac damage is the major limiting factor for the clinical use of doxorubicin (DOX). Preclinical studies indicate that inflammatory effects may be involved in DOX-induced cardiotoxicity. Nɛ-(carboxymethyl) lysine (CML) is suggested to be generated subsequent to oxidative stress, including inflammation. Therefore, the aim of this study was to investigate whether CML increased in the heart after DOX and whether anti-inflammatory agents reduced this effect in addition to their possible protection on DOX-induced cardiotoxicity. These effects were compared with those of the potential cardioprotector 7-monohydroxyethylrutoside (monoHER). BALB/c mice were treated with saline, DOX alone or DOX preceded by ketoprofen (KP), dexamethasone (DEX) or monoHER. Cardiac damage was evaluated according to Billingham. Nɛ-(carboxymethyl) lysine was quantified immunohistochemically.Compared to saline, a 21.6-fold increase of damaged cardiomyocytes was observed in mice treated with DOX (P<0.001). Addition of KP, DEX or monoHER before DOX significantly reduced the mean ratio of abnormal cardiomyocytes in comparison to mice treated with DOX alone (P⩽0.02). In addition, DOX induced a significant increase in the number of CML-stained intramyocardial vessels per mm2 (P=0.001) and also in the intensity of CML staining (P=0.001) compared with the saline-treated group. Nɛ-(carboxymethyl) lysine positivity was significantly reduced (P⩽0.01) by DOX-DEX, DOX-KP and DOX-monoHER. These results confirm that inflammation plays a role in DOX-induced cardiotoxicity, which is strengthened by the observed DOX-induced accumulation of CML, which can be reduced by anti-inflammatory agents and monoHER.

Caspase-dependent and -independent suppression of apoptosis by monoHER in Doxorubicin treated cells

Doxorubicin (DOX) is an antitumour agent for different types of cancer, but the dose-related cardiotoxicity limits its clinical use. To prevent this side effect we have developed the flavonoid monohydroxyethylrutoside (monoHER), a promising protective agent, which did not interfere with the antitumour activity of DOX. To obtain more insight in the mechanism underlying the selective protective effects of monoHER, we investigated whether monoHER (1 mM) affects DOX-induced apoptosis in neonatal rat cardiac myocytes (NeRCaMs), human endothelial cells (HUVECs) and the ovarian cancer cell lines A2780 and OVCAR-3. DOX-induced cell death was effectively reduced by monoHER in heart, endothelial and A2780 cells. OVCAR-3 cells were highly resistant to DOX-induced apoptosis. Experiments with the caspase-inhibitor zVAD-fmk showed that DOX-induced apoptosis was caspase-dependent in HUVECs and A2780 cells, whereas caspase-independent mechanisms seem to be important in NeRCaMs. MonoHER suppressed DOX-dependent activation of the mitochondrial apoptotic pathway in normal and A2780 cells as illustrated by p53 accumulation and activation of caspase-9 and -3 cleavage. Thus, monoHER acts by suppressing the activation of molecular mechanisms that mediate either caspase-dependent or -independent cell death. In light of the current work and our previous studies, the use of clinically achievable concentrations of monoHER has no influence on the antitumour activity of DOX whereas higher concentrations as used in the present study could influence the antitumour activity of DOX.

Isotoxic radiosurgery planning for brain metastases

PURPOSE/OBJECTIVE(S) Radionecrosis (RN) has previously been correlated with radiosurgery (RS) dose, lesion volume, and the volume of the brain receiving specific doses, i.e. V10-14Gy. A knowledge-based individualized estimation of the optimum RS dose has been derived based on lesional volume and brain toxicity parameters. METHODS AND MATERIALS A prediction model for brain toxicity parameters and estimation of the optimum RS dose was derived using 30 historical linac-based dynamic conformal arc RS plans for single brain metastases (BM) (0.2-20.3cc) with risk-adapted dose prescription ranging from 15 to 24Gy. Derivation of the model followed a three-step process: (1) Derivation of formulas for the prediction of brain toxicity parameters V10-18Gy; (2) Establishing the relationship of the coefficients used for the prediction of V12Gy with prescription dose; (3) Derivation of the optimum prescription dose for a given maximum V12Gy as a function of a given lesion volume. Model validation was performed on 65 new patients with 138 lesions (44 with multiple BM) treated with non-coplanar volumetric modulated stereotactic arc treatment (VMAT). RESULTS A linear dependence with the PTV size was found for all investigated brain toxicity parameters (V10-18Gy). Individualized RS prescription doses can be calculated for any given PTV size based on a linear relationship between V12Gy and PTV size, according to the formula PD=[V12Gy+0.96+(1.44×PTV)]/[0.12+(0.12×PTV)]. A very good correlation (R(2)=0.991) was found between the predicted V12Gy and the resulting V12Gy in 65 new patients with 138 lesions treated with non-coplanar VMAT technique in our clinic. CONCLUSIONS A simple formula is proposed for estimation of the optimal individual RS dose for any given lesion volume for patients with (multiple) BM. This formula is based on calculation of the brain toxicity parameter, V12Gy, for the normal brain minus PTV.

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 < 0.001) and 0.36 (p < 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 < 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.

Phase I clinical trial to determine the feasibility and maximum tolerated dose of panitumumab to standard gemcitabine-based chemoradiation in locally advanced pancreatic cancer

Purpose: Epidermal growth factor receptor (EGFR) inhibitors may improve both the therapeutic efficacy of radiotherapy and the radiosensitizing activity of gemcitabine. Based on this rationale and the nonoverlapping toxicity profiles of gemcitabine and the monoclonal EGFR antibody panitumumab, we designed a phase I trial to investigate the maximum-tolerated dose (MTD), safety, and activity of panitumumab added to gemcitabine-based chemoradiotherapy (CRT) in patients with locally advanced pancreatic cancer (LAPC). Experimental Design: Patients with LAPC and WHO performance status 0 to 1 were treated with weekly panitumumab at four dose levels (1–2.5 mg/kg), combined with weekly gemcitabine 300 mg/m2 and radiotherapy (50.4 Gy in 28 fractions) for 6 weeks, followed by gemcitabine 1,000 mg/m2 weekly for 3 weeks every 4 weeks until disease progression or unacceptable toxicity. Each cohort was monitored during the combination therapy to establish dose limiting toxicity. Tumor evaluation was performed after CRT and during gemcitabine monotherapy. Results: Fourteen patients were enrolled; 14 were evaluable for toxicity and 13 for response. The MTD for panitumumab was 1.5 mg/kg. Three of the 6 patients, treated at MTD, experienced grade 3 adverse events during the combination therapy; neutropenia (n = 2; 33%), fatigue (n = 1; 17%), nausea (n = 1; 17%), and vomiting (n = 1; 17%). Partial response was achieved by 3 patients (23%), 1 in each dose cohort. Median progression free survival of the three cohorts together was 8.9 months. Conclusions: The addition of panitumumab to gemcitabine-based chemoradiotherapy in LAPC has manageable toxicity and potential clinical efficacy. Clin Cancer Res; 21(20); 4569–75. ©2015 AACR.

OC-0425: Clinical experience with stereotactic MR-guided adaptive radiation therapy for pancreatic tumors

Purpose or Objective The duodenum is the primary dose-limiting organ when performing SBRT for locally advanced pancreatic cancer (LAPC). With technical and imaging advancements, the incidence of grade ≥3 small bowel toxicity (bleeding, perforation, strictures) has decreased to

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 (<3months) and long-term survival (>12months) 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 1year 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.

Patient-reported Outcome Measurements on the Tolerance of Magnetic Resonance Imaging-guided Radiation Therapy

Purpose Magnetic resonance imaging-guided radiation therapy (MRgRT) requires patient positioning within the MR bore and prolonged MR imaging during delivery, both of which are new in radiation oncology. Patient tolerance of MRgRT was prospectively evaluated using patient-reported outcome questionnaires (PRO-Q). Methods Our MRgRT procedure involves daily high-resolution MR scanning, limited re-contouring, daily plan re-optimization, quality assurance (QA), and gated delivery. Patients with claustrophobia are excluded. Mean fraction duration was 45 and 60 minutes for stereotactic treatments during free-breathing and breath-hold, respectively. Patient-controlled video-feedback was used for breath-hold delivery. PRO-Qs collected in the first 150 patients treated included questions on MR-related complaints and also evaluated aspects of active participation. Results Almost one-third of patients (29%) scored at least one PRO-Q item on MR-related complaints as ‘moderate’ or ‘very much’, with noise, feeling cold, and paresthesia being the most frequently scored in this way. Considerable anxiety was reported by 5%, but no medication was required for this in any patient. Patient participation in video feedback for breath-hold delivery was appreciated by the majority of patients, all of whom completed the procedure. Only 5% of patients considered treatment duration to be unacceptably long. Conclusion Despite the lengthy MRgRT procedure, outcomes of PRO-Q indicate that it was well-tolerated by patients.

Whole brain radiotherapy for brain metastases from non-small cell lung cancer: the end of an era?

Up to 30−50% of patients with non-small cell lung cancer (NSCLC) will at some point in their course of disease develop brain metastases (1,2). In selected patients, local aggressive treatment in the form of surgery or radiosurgery may be indicated; however, particularly patients with large volume metastatic brain disease have traditionally been treated with whole brain radiotherapy (WBRT). Although the general belief is that WBRT results in symptom palliation, decrease of steroid needs and even survival prolongation, up till now the evidence for such benefit of WBRT over best supportive care has been largely lacking, with the exception of a small Radiation Therapy Oncology Group (RTOG) study in the early 1980’s (3).