Andra Krauze

Bringing the heavy: carbon ion therapy in the radiobiological and clinical context

Radiotherapy for the treatment of cancer is undergoing an evolution, shifting to the use of heavier ion species. For a plethora of malignancies, current radiotherapy using photons or protons yields marginal benefits in local control and survival. One hypothesis is that these malignancies have acquired, or are inherently radioresistant to low LET radiation. In the last decade, carbon ion radiotherapy facilities have slowly been constructed in Europe and Asia, demonstrating favorable results for many of the malignancies that do poorly with conventional radiotherapy. However, from a radiobiological perspective, much of how this modality works in overcoming radioresistance, and extending local control and survival are not yet fully understood. In this review, we will explain from a radiobiological perspective how carbon ion radiotherapy can overcome the classical and recently postulated contributors of radioresistance (α/β ratio, hypoxia, cell proliferation, the tumor microenvironment and metabolism, and cancer stem cells). Furthermore, we will make recommendations on the important factors to consider, such as anatomical location, in the future design and implementation of clinical trials. With the existing data available we believe that the expansion of carbon ion facilities into the United States is warranted.

Chemoirradiation for Glioblastoma Multiforme: The National Cancer Institute Experience

Purpose Standard treatment for glioblastoma (GBM) is surgery followed by radiation (RT) and temozolomide (TMZ). While there is variability in survival based on several established prognostic factors, the prognostic utility of other factors such as tumor size and location are not well established. Experimental Design The charts of ninety two patients with GBM treated with RT at the National Cancer Institute (NCI) between 1998 and 2012 were retrospectively reviewed. Most patients received RT with concurrent and adjuvant TMZ. Topographic locations were classified using preoperative imaging. Gross tumor volumes were contoured using treatment planning systems utilizing both pre-operative and post-operative MR imaging. Results At a median follow-up of 18.7 months, the median overall survival (OS) and progression-free survival (PFS) for all patients was 17.9 and 7.6 months. Patients with the smallest tumors had a median OS of 52.3 months compared to 16.3 months among patients with the largest tumors, P = 0.006. The patients who received bevacizumab after recurrence had a median OS of 23.3 months, compared to 16.3 months in patients who did not receive it, P = 0.0284. The median PFS and OS in patients with periventricular tumors was 5.7 and 17.5 months, versus 8.9 and 23.3 months in patients with non-periventricular tumors, P = 0.005. Conclusions Survival in our cohort was comparable to the outcome of the defining EORTC-NCIC trial establishing the use of RT+TMZ. This study also identifies several potential prognostic factors that may be useful in stratifying patients.

Brain tumor segmentation using holistically nested neural networks in MRI images

Purpose: Gliomas are rapidly progressive, neurologically devastating, largely fatal brain tumors. Magnetic resonance imaging (MRI) is a widely used technique employed in the diagnosis and management of gliomas in clinical practice. MRI is also the standard imaging modality used to delineate the brain tumor target as part of treatment planning for the administration of radiation therapy. Despite more than 20 yr of research and development, computational brain tumor segmentation in MRI images remains a challenging task. We are presenting a novel method of automatic image segmentation based on holistically nested neural networks that could be employed for brain tumor segmentation of MRI images. Methods: Two preprocessing techniques were applied to MRI images. The N4ITK method was employed for correction of bias field distortion. A novel landmark‐based intensity normalization method was developed so that tissue types have a similar intensity scale in images of different subjects for the same MRI protocol. The holistically nested neural networks (HNN), which extend from the convolutional neural networks (CNN) with a deep supervision through an additional weighted‐fusion output layer, was trained to learn the multiscale and multilevel hierarchical appearance representation of the brain tumor in MRI images and was subsequently applied to produce a prediction map of the brain tumor on test images. Finally, the brain tumor was obtained through an optimum thresholding on the prediction map. Results: The proposed method was evaluated on both the Multimodal Brain Tumor Image Segmentation (BRATS) Benchmark 2013 training datasets, and clinical data from our institute. A dice similarity coefficient (DSC) and sensitivity of 0.78 and 0.81 were achieved on 20 BRATS 2013 training datasets with high‐grade gliomas (HGG), based on a two‐fold cross‐validation. The HNN model built on the BRATS 2013 training data was applied to ten clinical datasets with HGG from a locally developed database. DSC and sensitivity of 0.83 and 0.85 were achieved. A quantitative comparison indicated that the proposed method outperforms the popular fully convolutional network (FCN) method. In terms of efficiency, the proposed method took around 10 h for training with 50,000 iterations, and approximately 30 s for testing of a typical MRI image in the BRATS 2013 dataset with a size of 160 × 216 × 176, using a DELL PRECISION workstation T7400, with an NVIDIA Tesla K20c GPU. Conclusions: An effective brain tumor segmentation method for MRI images based on a HNN has been developed. The high level of accuracy and efficiency make this method practical in brain tumor segmentation. It may play a crucial role in both brain tumor diagnostic analysis and in the treatment planning of radiation therapy.

The evolving role for re-irradiation in the management of recurrent grade 4 glioma

Although significant gains have been realized in the management of grade 4 glioma, the majority of these patients will ultimately suffer local recurrence within the prior field of treatment. Clearly, novel local treatment strategies are required to improve patient outcomes. Concerns of toxicity have limited enthusiasm for the utilization of re-irradiation as a treatment option. However, using modern imaging technology and precision radiotherapy delivery techniques re-irradiation has proven a feasible option achieving both a palliative benefit and prolongation of survival with low toxicity rates. The evolution of re-irradiation as a treatment modality for recurrent grade 4 glioma is reviewed. In addition, potential targeted radiosensitizers to be used in conjunction with re-irradiation are also discussed.

Effect of Prostate Magnetic Resonance Imaging/Ultrasound Fusion-guided Biopsy on Radiation Treatment Recommendations

PURPOSE Targeted magnetic resonance imaging (MRI)/ultrasound fusion prostate biopsy (MRI-Bx) has recently been compared with the standard of care extended sextant ultrasound-guided prostate biopsy (SOC-Bx), with the former associated with an increased rate of detection of clinically significant prostate cancer. The present study sought to determine the influence of MRI-Bx on radiation therapy and androgen deprivation therapy (ADT) recommendations. METHODS AND MATERIALS All patients who had received radiation treatment and had undergone SOC-Bx and MRI-Bx at our institution were included. Using the clinical T stage, pretreatment prostate-specific antigen, and Gleason score, patients were categorized into National Comprehensive Cancer Network risk groups and radiation treatment or ADT recommendations assigned. Intensification of the recommended treatment after multiparametric MRI, SOC-Bx, and MRI-Bx was evaluated. RESULTS From January 2008 to January 2016, 73 patients received radiation therapy at our institution after undergoing a simultaneous SOC-Bx and MRI-Bx (n=47 with previous SOC-Bx). Repeat SOC-Bx and MRI-Bx resulted in frequent upgrading compared with previous SOC-Bx (Gleason score 7, 6.7% vs 44.6%; P<.001; Gleason score 8-10, 2.1% vs 38%; P<.001). MRI-Bx increased the proportion of patients classified as very high risk from 24.7% to 41.1% (P=.027). Compared with SOC-Bx alone, including the MRI-Bx findings resulted in a greater percentage of pathologically positive cores (mean 37% vs 44%). Incorporation of multiparametric MRI and MRI-Bx results increased the recommended use and duration of ADT (duration increased in 28 of 73 patients and ADT was added for 8 of 73 patients). CONCLUSIONS In patients referred for radiation treatment, MRI-Bx resulted in an increase in the percentage of positive cores, Gleason score, and risk grouping. The benefit of treatment intensification in accordance with the MRI-Bx findings is unknown.

Abstract 1433: A mobile app for health related quality of life and symptom assessment in patients with primary brain tumors in an outpatient oncology clinic

Purpose: Primary brain tumors, and their treatments, can have a significant impact on patient quality of life due to altered mentation, mood changes, memory loss, and neurologic deficits. It has therefore been suggested that patient related outcomes need to be included as endpoints for treatment efficacy. The objective of this project was to develop and evaluate a mobile application (GlioNCI), in reporting health-related quality of life measures and symptom scoring in patients with primary brain tumors treated and followed in an outpatient oncology clinic. Experimental Procedures and Results: Apple9s Xcode Integrated Development Environment (IDE) was used to develop GlioNCI using the Swift programming language. The parameters and scores chosen had previously been validated in primary CNS tumors. Medication and steroid use is captured at each encounter, as are seizure characteristics, frequency and management. Health related quality of life questionnaires included portions of the EORTC QLQ-C30, and EORTC QLQ-BN20, and MD Anderson Symptom Inventory Brain Tumor Module, which have been validated in patients with cancer and primary CNS tumors respectively. Patients’ symptoms and effects on function are collected with the Activities of Daily Living scale, and the Instrumental Activities of Daily Living Scale. Mood and mental state were addressed using the Hospital Anxiety and Depression Scale. Separate questionnaires for different encounters and time points in outpatient treatment were included to assess care provider, as well as patient related measures, allowing for flexibility of the app to the needs of both. A mobile app was developed to collect, and archive in a database, input and feedback from both patients and care providers in oncology clinics. Conclusion: The creation of a patient centered quality of life and symptom assessment mobile app, following patients with primary brain tumors over their course of treatment and in follow-up is feasible. Pilot testing and patient evaluation of the application in an oncology clinic will be used to validate GlioNCI as a tool in outpatient clinics. Citation Format: Lindsay Rowe, Tuo Dong, Terri Armstrong, Megan Mackey, Mark Gilbert, Andra Krauze, Kevin Camphausen. A mobile app for health related quality of life and symptom assessment in patients with primary brain tumors in an outpatient oncology clinic. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1433.

Late toxicity in long-term survivors from a phase 2 study of concurrent radiation therapy, temozolomide and valproic acid for newly diagnosed glioblastoma

Background Valproic acid (VPA) is an antiepileptic agent with histone deacetylase inhibitor activity shown to enhance overall survival and progression free survival in patients with newly diagnosed glioblastoma (GBM). This reports on the late toxicity of the VPA/radiotherapy (RT)/temozolomide (TMZ) combination in the long-term survivors of a phase 2 study evaluating this regimen. Methods 37 patients with newly diagnosed GBM were initially enrolled on this trial and received combination therapy. VPA/RT/TMZ related late toxicities were evaluated in the 6 patients that lived greater than 3 years using the Cancer Therapy and Evaluation Program Common Toxicity Criteria (CTC) Version 4.0 for toxicity and adverse event reporting as well as the RTOG/EORTC Radiation Morbidity Scoring Scheme. Results The median duration of follow-up for these 6 patients was 69.5m. In this cohort, the median OS was 73.8m (60.8-103.8m) and median PFS was 53.1m (37.3 - 103.8m). The most common late toxicity of VPA in conjunction with RT/TMZ were the CTC classifications of neurological, pain, and blood/ bone marrow toxicity and most were grade 1/2. There were only two grade 3/4 toxicities. Conclusions The addition of VPA to concurrent RT/TMZ in patients with newly diagnosed GBM was well tolerated with little late toxicity. Additionally, VPA may result in improved outcomes as compared to historical data and merits further study.

Differentiating pseudoprogression from true progression: analysis of radiographic, biologic, and clinical clues in GBM

IntroductionPseudoprogression (PsP) is a diagnostic dilemma in glioblastoma (GBM) after chemoradiotherapy (CRT). Magnetic resonance imaging (MRI) features may fail to distinguish PsP from early true progression (eTP), however clinical findings may aid in their distinction.MethodsSixty-seven patients received CRT for GBM between 2003 and 2016, and had pre- and post-treatment imaging suitable for retrospective evaluation using RANO criteria. Patients with signs of progression within the first 12-weeks post-radiation (P-12) were selected. Lesions that improved or stabilized were defined as PsP, and lesions that progressed were defined as eTP.ResultsThe median follow up for all patients was 17.6 months. Signs of progression developed in 35/67 (52.2%) patients within P-12. Of these, 20/35 (57.1%) were subsequently defined as eTP and 15/35 (42.9%) as PsP. MRI demonstrated increased contrast enhancement in 84.2% of eTP and 100% of PsP, and elevated CBV in 73.7% for eTP and 93.3% for PsP. A decrease in FLAIR was not seen in eTP patients, but was seen in 26.7% PsP patients. Patients with eTP were significantly more likely to require increased steroid doses or suffer clinical decline than PsP patients (OR 4.89, 95% CI 1.003–19.27; p = 0.046). KPS declined in 25% with eTP and none of the PsP patients.ConclusionsMRI imaging did not differentiate eTP from PsP, however, KPS decline or need for increased steroids was significantly more common in eTP versus PsP. Investigation and standardization of clinical assessments in response criteria may help address the diagnostic dilemma of pseudoprogression after frontline treatment for GBM.

Multiparametric MRI for the detection of local recurrence of prostate cancer in the setting of biochemical recurrence after low dose rate brachytherapy

PURPOSE Prostate multiparametric magnetic resonance imaging (mpMRI) has utility in detecting post-radiotherapy local recurrence. We conducted a multireader study to evaluate the diagnostic performance of mpMRI for local recurrence after low dose rate (LDR) brachytherapy. METHODS A total of 19 patients with biochemical recurrence after LDR brachytherapy underwent 3T endorectal coil mpMRI with T2-weighted imaging, dynamic contrast-enhanced imaging (DCE) and diffusion-weighted imaging (DWI) with pathologic confirmation. Prospective reads by an experienced prostate radiologist were compared with reads from 4 radiologists of varying experience. Readers identified suspicious lesions and rated each MRI detection parameter. MRI-detected lesions were considered true-positive with ipsilateral pathologic confirmation. Inferences for sensitivity, specificity, positive predictive value (PPV), kappa, and index of specific agreement were made with the use of bootstrap resampling. RESULTS Pathologically confirmed recurrence was found in 15 of 19 patients. True positive recurrences identified by mpMRI were frequently located in the transition zone (46.7%) and seminal vesicles (30%). On patient-based analysis, average sensitivity of mpMRI was 88% (standard error [SE], 3.5%). For highly suspicious lesions, specificity of mpMRI was 75% (SE, 16.5%). On lesion-based analysis, the average PPV was 62% (SE, 6.7%) for all lesions and 78.7% (SE, 10.3%) for highly suspicious lesions. The average PPV for lesions invading the seminal vesicles was 88.8% (n=13). The average PPV was 66.6% (SE, 5.8%) for lesions identified with T2-weighted imaging, 64.9% (SE, 7.3%) for DCE, and 70% (SE, 7.3%) for DWI. CONCLUSION This series provides evidence that mpMRI after LDR brachytherapy is feasible with a high patient-based cancer detection rate. Radiologists of varying experience demonstrated moderate agreement in detecting recurrence.

Abstract LB-059: Neoadjuvant immunotherapy with androgen deprivation therapy (ADT) prior to radiation in prostate cancer: Impact on multiparametric prostate MRI and immune responses

Background: There is increasing interest in using combination immunotherapy in the neoadjuvant setting in prostate cancer, however, endpoints for such studies remain elusive. We have conducted a clinical trial evaluating immunotherapy with ADT in patients with high risk prostate cancer. Patients were assessed for immune responses and changes in endorectal (er) MRI which can be used to assess intraprostatic tumors. Methods: Treatment-naive high-risk (Gleason 8-10, PSA>20, or stage T3) prostate cancer patients (pts) were randomized to standard ADT+Radiation + an immunotherapy targeting MUC1 (tecemotide, aka L-BLP25) in this trial (NCT01496131). ADT consisted of gonadotropin-releasing hormone therapy. Immunotherapy included low dose (300 mg/m2, maximum 600 mg) pre-treatment cyclophosphamide for regulatory T-cell depletion. erMRI was done at baseline and after 2 months of immunotherapy including multiparametric MRI evaluation of apparent diffusion coefficient (ADC) maps from diffusion-weighted MRI. Monthly peripheral blood assessments analyzed immune cell subsets using flow cytometry and intracellular cytokine (ICC) staining for MUC-1 specific responses. Results: 28 pts with high risk prostate cancer were enrolled (n=14/arm). As expected, PSA declined in all pts 2 months after ADT. erMRI after 2 months of treatment suggested greater improvements in ADC values in pts receiving immunotherapy+ADT vs. ADT alone. Improved ADC on MRI indicates increased intratumoral diffusion and has been associated with decreased tumor density. The improvements in ADC were seen when one dominant tumor per patient was evaluated (p=0.17) but were more pronounced when up to 3 lesions were evaluated per pt (n=44 lesions; p=0.031). Compared to baseline, there were trends to increases in CTLA4+ CD8+ T-cells consistent with immune activation and decreases in myeloid derived suppressor cells (MDSCs) in pts receiving immunotherapy+ADT coinciding with the erMRI changes. These immune findings were not seen in the ADT alone group. 3 of 14 pts had MUC1 specific immune response by ICC. 2 of these patients had the greatest changes in ADC noted on erMRI over a 2-year period. Conclusions: Based on assessments by erMRI, pts who received ADT+immunotherapy had greater improvements in ADC than pts receiving ADT alone. Given that ADC improvements are associated with decreased tumor density, this suggests a possible greater anti-tumor effect of the ADT-immunotherapy combination vs. ADT alone. These findings were associated with trends to increased activated CD8+ T-cells and decreased MDSCs in pts receiving immunotherapy+ADT, with 3/14 pts having MUC1 specific immune responses. Further studies are required to confirm the potential to use ADC on erMRI as a potential (bio)marker of anti-tumor effect of immune combinations including ADT. Citation Format: Ravi A. Madan, Baris Turkbey, Lauren M. Lepone, Renee N. Donahue, Italia Grenga, Samuel Samuel Borofsky, Peter A. Pinto, Deborah Citrin, Aradhana Kaushal, Andra Krauze, Sheri McMahon, Myrna Rauchhorst, Anna Couvillon, Martin H. Falk, S Peter Eggleton, Stephen C. Greco, Peter L. Choyke, William L. Dahut, Jeffrey Schlom, James L. Gulley. Neoadjuvant immunotherapy with androgen deprivation therapy (ADT) prior to radiation in prostate cancer: Impact on multiparametric prostate MRI and immune responses [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-059. doi:10.1158/1538-7445.AM2017-LB-059