Steve Walston

Improving Intra-Fractional Target Position Accuracy Using a 3D Surface Surrogate for Left Breast Irradiation Using the Respiratory-Gated Deep-Inspiration Breath- Hold Technique

Purpose To evaluate the use of 3D optical surface imaging as a surrogate for respiratory gated deep-inspiration breath-hold (DIBH) for left breast irradiation. Material and Methods Patients with left-sided breast cancer treated with lumpectomy or mastectomy were selected as candidates for DIBH treatment for their external beam radiation therapy. Treatment plans were created on both free breathing (FB) and DIBH computed tomography (CT) simulation scans to determine dosimetric benefits from DIBH. The Real-time Position Management (RPM) system was used to acquire patients breathing trace during DIBH CT acquisition and treatment delivery. The reference 3D surface models from FB and DIBH CT scans were generated and transferred to the “AlignRT” system for patient positioning and real-time treatment monitoring. MV Cine images were acquired during treatment for each beam as quality assurance for intra-fractional position verification. The chest wall excursions measured on these images were used to define the actual target position during treatment, and to investigate the accuracy and reproducibility of RPM and AlignRT. Results Reduction in heart dose can be achieved using DIBH for left breast/chest wall radiation. RPM was shown to have inferior correlation with the actual target position, as determined by the MV Cine imaging. Therefore, RPM alone may not be an adequate surrogate in defining the breath-hold level. Alternatively, the AlignRT surface imaging demonstrated a superior correlation with the actual target positioning during DIBH. Both the vertical and magnitude real-time deltas (RTDs) reported by AlignRT can be used as the gating parameter, with a recommended threshold of ±3 mm and 5 mm, respectively. Conclusion The RPM system alone may not be sufficient for the required level of accuracy in left-sided breast/CW DIBH treatments. The 3D surface imaging can be used to ensure patient setup and monitor inter- and intra- fractional motions. Furthermore, the target position accuracy during DIBH treatment can be improved by AlignRT as a superior surrogate, in addition to the RPM system.

A multi-institutional experience in pediatric high-grade glioma.

Introduction: Pediatric high-grade gliomas are rare tumors with poor outcomes and incompletely defined management. We conducted a multi-institutional retrospective study to evaluate association of clinical, pathologic, and treatment characteristics with outcomes. Materials and methods: Fifty-one patients treated from 1984 to 2008 at the Ohio State University or University of Michigan were included. Histologic subgroups were compared. Log-rank and stepwise Cox proportional hazard modeling were used to analyze progression-free survival (PFS) and overall survival (OS) within the whole group, grade III subgroup, grade IV subgroup, and sub-total resection/biopsy subgroup. Results: Median OS was 27.6 months. Grade III histology, complete tumor resection, and cerebral tumor location correlated with improved PFS and OS. Temozolomide use and chemotherapy after radiotherapy or chemoradiation (CRT) were associated with better PFS while seizure at presentation was associated with better OS. In multivariate analysis, complete resection and chemotherapy following radiotherapy or CRT were independent predictors for improved PFS and OS. For grade III and IV subgroups, complete resection was associated with improved OS (grade III) and seizure presentation was associated with improved OS (grade IV). In the incompletely resection subgroup, temozolomide use and concurrent CRT independently correlated with improved PFS, while higher radiation dose (≥59.4 Gy) and adjuvant chemotherapy were independently associated with improved OS. Discussion: Total resection and receiving chemotherapy adjuvant to radiation or CRT are most closely associated with improved PFS and OS. For higher risk incompletely resected patients, temozolomide use and treatment intensification with concurrent CRT, adjuvant chemotherapy, and higher radiation dose were associated with improved outcomes.

Perineural Invasion Predicts for Distant Metastasis in Locally Advanced Rectal Cancer Treated With Neoadjuvant Chemoradiation and Surgery

Objectives: The benefit of adjuvant chemotherapy in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (nCRT) and surgery is controversial. We examined the association of perineural invasion (PNI) with outcomes to determine whether PNI could be used to risk-stratify patients. Materials and Methods: We performed a retrospective study of 110 patients treated with nCRT and surgery for LARC at our institution from 2004 to 2011. Eighty-seven patients were identified in our final analysis. We evaluated the association of PNI with locoregional control, distant metastasis-free survival (DMFS), disease-free survival (DFS), and overall survival, using log-rank and Cox proportional hazard modeling. Results: Fourteen patients (16%) were PNI+ and 73 patients (84%) were PNI−. The median follow-up was 27 months (range, 0.9 to 84 mo). The median DMFS was 13.5 months for PNI+ and median not reached (>40 mo) for PNI− (P<0.0001). The median DFS was 13.5 months for PNI+ and 39.8 months for PNI− (P<0.0001). In a multivariate model including 7 pathologic variables, type of surgery, time to surgery from end of nCRT, and use of adjuvant chemotherapy, PNI remained a significant independent predictor of DMFS (hazard ratio 9.79; 95% confidence interval, 3.48-27.53; P<0.0001) and DFS (hazard ratio 5.72; 95% confidence interval, 2.2-14.9; P=0.0001). Conclusions: For patients with LARC treated with nCRT, PNI found at the time of surgery is significantly associated with worse DMFS and DFS. Our data support testing the role of adjuvant chemotherapy in patients with PNI and perhaps other high-risk features.

Dosimetric Considerations in Respiratory-Gated Deep Inspiration Breath-Hold for Left Breast Irradiation.

Purpose: To present our clinical workflow of incorporating AlignRT for left breast deep inspiration breath-hold treatments and the dosimetric considerations with the deep inspiration breath-hold protocol. Material and Methods: Patients with stage I to III left-sided breast cancer who underwent lumpectomy or mastectomy were considered candidates for deep inspiration breath-hold technique for their external beam radiation therapy. Treatment plans were created on both free-breathing and deep inspiration breath-hold computed tomography for each patient to determine whether deep inspiration breath-hold was beneficial based on dosimetric comparison. The AlignRT system was used for patient setup and monitoring. Dosimetric measurements and their correlation with chest wall excursion and increase in left lung volume were studied for free-breathing and deep inspiration breath-hold plans. Results: Deep inspiration breath-hold plans had significantly increased chest wall excursion when compared with free breathing. This change in geometry resulted in reduced mean and maximum heart dose but did not impact lung V20 or mean dose. The correlation between chest wall excursion and absolute reduction in heart or lung dose was found to be nonsignificant, but correlation between left lung volume and heart dose showed a linear association. It was also identified that higher levels of chest wall excursion may paradoxically increase heart or lung dose. Conclusion: Reduction in heart dose can be achieved for many left-sided breast and chest wall patients using deep inspiration breath-hold. Chest wall excursion as well as left lung volume did not correlate with reduction in heart dose, and it remains to be determined what metric will provide the most optimal and reliable dosimetric advantage.

Molecular profiling of locally-advanced rectal adenocarcinoma using microRNA expression (Review)

Treatment for locally-advanced rectal cancer (LARC) typically consists of neoadjuvant chemoradiation followed by total mesorectal excision. Recently, there has been growing interest in non-operative management for patients who are medically-inoperable or wish to avoid surgical morbidity and permanent colostomy. Approximately 50% of patients who receive pre-operative neoadjuvant chemoradiation develop some degree of pathologic response. Approximately 10-20% of patients are found to have a complete pathologic response, a finding which has frequently been shown to predict better clinical outcomes, including local-regional control, distant metastasis and survival. Many recent studies have evaluated the role of molecular biomarkers in predicting response to neoadjuvant therapy. MicroRNAs (miRNAs) are an emerging class of biomarkers that have the potential to predict which patients are most likely to benefit from pre-operative therapy and from a selective surgical approach. Here, we review the published literature on microRNAs as prognostic and predictive biomarkers in rectal cancer after pre-operative therapy. In the future, the development of prospectively validated miRNA signatures will allow clinical implementation of miRNAs as prognostic and predictive signatures in LARC.

Clinical outcomes and prognostic factors in cisplatin versus cetuximab chemoradiation for locally advanced p16 positive oropharyngeal carcinoma

OBJECTIVES Randomized trials evaluating cisplatin versus cetuximab chemoradiation (CRT) for p16+ oropharyngeal cancer (OPC) have yet to report preliminary data. Meanwhile, as a preemptive step toward morbidity reduction, the off-trial use of cetuximab in p16+ patients is increasing, even in those who could potentially tolerate cisplatin. The purpose of this study was to compare the efficacy of cisplatin versus cetuximab CRT in the treatment of p16+ OPC and to identify prognostic factors and predictors of tumor response. MATERIALS AND METHODS Cases of p16+ OPC treated with cisplatin or cetuximab CRT at our institution from 2010 to 2014 were identified. Recursive partitioning analysis (RPA) classification was used to determine low-risk (LR-RPA) and intermediate-risk (IR-RPA) groups. Log-rank/Kaplan-Meier and Cox Regression methods were used to compare groups. RESULTS We identified 205 patients who received cisplatin (n = 137) or cetuximab (n = 68) CRT in the definitive (n = 178) or postoperative (n = 27) setting. Median follow-up was 3 years. Cisplatin improved 3-year locoregional control (LRC) [92.7 vs 65.4%], distant metastasis-free survival (DMFS) [88.3 vs 71.2%], recurrence-free survival (RFS) [86.6 vs 50.6%], and overall survival (OS) [92.6 vs 72.2%] compared to cetuximab [all p < .001]. Concurrent cisplatin improved 3-year OS for LR-RPA (97.1 vs 80.3%, p < .001) and IR-RPA (97.1 vs 80.3%, p < .001) groupings. CONCLUSION When treating p16+ OPC with CRT, the threshold for substitution of cisplatin with cetuximab should be maintained appropriately high in order to prolong survival times and optimize locoregional and distant tumor control. When cetuximab is used in cisplatin-ineligible patients, altered fractionation RT should be considered in an effort to improve LRC.

MicroRNA molecular profiling identifies potential signaling pathways conferring resistance to chemoradiation in locally-advanced rectal adenocarcinoma

Purpose There has been growing interest in using chemoradiation (CRT) for non-operative management of rectal cancer, and identifying patients who might benefit most from this approach is crucial. This study identified miRNAs (miRs) associated with clinical outcomes and treatment resistance by evaluating both pre- and post-CRT expression profiles. Methods Forty patients, 9 with pathologic complete response (pCR) and 31 with pathologic incomplete response (pIR) were included. MicroRNA was extracted from 40 pre-therapy tumor samples and 31 post-chemoradiation surgical samples with pathologic incomplete response (pIR). A generalized linear model was used to identify miRs associated with pCR. A linear mixed effects model was used to identify miRs differentially expressed before and after treatment. miR expression was dichotomized at the mean and clinical outcomes were evaluated using Cox proportional hazard modeling. Results Nine miRs were associated with pCR (p<0.05), but none were significant after false discovery rate correction. Among patients with pIR, 68 miRs were differentially expressed between the pre and post-CRT groups (FDR p<0.05). Ingenuity pathway analysis (IPA) demonstrated multiple signaling networks associated with pIR, including p38MAPK, TP53, AKT, IL-6, and RAS. Increased let-7b was correlated with increased distant metastasis (DM), worse relapse-free survival (RFS), and worse overall survival (OS) (p<0.05). Conclusions No miRs were significantly correlated with pCR. We identified miRs that were differentially expressed between pre- and post-CRT tumor samples, and these miRs implicated multiple signaling pathways that may confer resistance to CRT. In addition, we identified an association between increased let-7b and worse clinical outcomes (DM, DFS, OS).

Use of Neuroimaging for Radiation Therapy Planning

Intracranial tumors, both primary and metastatic, have distinct anatomic and neuroimaging features. Radiotherapy is often used in the management of intracranial tumors. Various techniques used in radiotherapy include external beam radiotherapy and stereotactic radiotherapy. This chapter discusses the use of neuroimaging in tumor delineation and radiation planning and delivery. Evaluation of immobilization, target volumes, normal tissue volumes, plan review, and quality assurance is required to safely deliver radiotherapy. The practical review of radiotherapy in high-grade glioma is used to demonstrate these facets of patient care. Neuroimaging and clinical evaluation are used to evaluate for disease recurrence following treatment completion. On standard magnetic resonance imaging, it may be difficult to differentiate between pseudo-progression, true disease progression, and radiation necrosis. A multitude of imaging techniques are now available to assist in making this distinction. The progress in neuroimaging has improved radiation planning and delivery and will continue to do so in the future.

Abstract LB-6: Exploring nicotinamide-N-methyltransferase kinetics through targeted metabolomic profiling for its prognostic value in glioblastoma

Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Purpose: Glioblastoma (GBM) is the most aggressive form of glioma. With average patient survival of about 14 months, largely due to its resistance to conventional therapies, there is opportunity for significant improvements to care. Nicotinamide-N-methyltransferase (NNMT) is an enzyme responsible for the methylation of Nicotinamide and other xenobiotic compounds. Although NNMTs exact role in the malignant phenotype remains poorly understood, it has been investigated for its potential use as a prognostic marker or therapeutic target in other cancers. It is detected at very low levels in normal brain tissue but at significantly higher levels in GBM. Additionally, Kaplan-Meier plots from publically available data sets suggest that higher NNMT expression is correlated with adverse patient outcome. In addition to gene interference and various functional assays, we employed a targeted metabolomic approach, using LC-MS Quadropole Time of Flight (Q-TOF) and LC-MS Triple Quad (QQQ) instruments to study intracellular levels of Nicotinamide and N-methylnicotinamide to gain a better understanding of NNMTs role in GBM. Methods: We determined the expression profile of NNMT in established (ATCC) and in our panel of patient derived, primary GBM cell lines. By generating an NNMT isogenic model in U87 cells, we were able to study the functional consequences of differential NNMT expression using in vitro assays such as MTS Assay, Clonogenic Survival Assay, Annexin V, ATP Assay, Comet Assay, and Western Blotting. We intracranially injected NOD-SCID mice with U87 NNMT cells to assess differences in tumorgenicity in vivo. We have also used LC-MS Quadropole Time of Flight (Q-TOF) and LC-MS Triple Quad (QQQ) instruments to measure intracellular levels of the metabolites relevant to NNMT enzymatic function. Results and Conclusions: Results indicate that NNMT protein is highly expressed in primary cell lines. Encouragingly, U87 NNMT Knockdown cells are less proliferative, more sensitive to radiation in vitro, and are less tumorgenic in vivo. Recapitulating the clinical observations, these results could justify why clinically patients with lower expression of NNMT enjoyed increased overall survival. These results also suggest that finding ways to decrease NNMT in patients tumors may improve response to radiation. Additional preliminary results indicate that intracellular N-methylnicotinamide levels correlate directly with NNMT protein expression and could be used a surrogate biomarker for intracellular NNMT levels, potentially predicting not only overall survival but perhaps response to radiation. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-6. doi:1538-7445.AM2012-LB-6

Abstract 2504: Genetic and molecular profiles altering radiosensitivity in melanoma

Purpose/Objectives: Historically, melanoma has been considered a relatively radioresistant tumor. Newer data have challenged this viewpoint, and radiation therapy (RT) is now considered to be useful for treating patients with malignant melanoma. Most importantly, it can provide effective palliation for the 40 to 50 percent of patients who develop unresectable locally recurrent or metastatic disease producing bone pain, epidural spinal cord compression, central nervous system dysfunction due to brain involvement, and/or tumor hemorrhage. RT has also been applied after complete excision of a primary melanoma or after therapeutic lymphadenectomy for regional nodal disease as adjuvant therapy to reduce the rate of local recurrence for certain types of melanoma. Melanoma is the most lethal form of skin cancer and incidences in the United States have steadily increased over the past 30 years. According to the American Cancer Society, melanoma accounts for only 3 percent of all skin cancers, but is responsible for nearly 74 percent of the deaths resulting from skin cancer. Prognosis is particularly poor for patients with metastasis as only 15 percent of this patient population survives for more than 5 years. Melanoma has been regarded as resistant to most treatments including radiation therapy. Melanoma has been poorly studied from the perspective of radiation biology and it is our intentions to elucidate key molecular mechanisms that can improve the benefit of radiotherapy in melanoma. Materials/Methods: In this study we set out to study genes that are commonly mutated in melanoma: BRAF, N-RAS, CKIT, TP53, PTEN, etc. These genes were sequenced in our panel of melanoma cell lines for determination of mutational status. We then stratified the cell lines based on their response to radiation as measured in a clonogenic survival and other functional assays. Established (ATCC) and primary (OSUMC patients) cell lines were used in this study. From the radioresistant melanoma cell lines we were able to isolate a small subpopulation of cells which exhibited the properties of stem cells and currently we are conducting further studies to completely characterize this sub population. Results/Conclusion: Melanoma has been poorly studied from the perspective of radiation biology and it is our intentions to elucidate key molecular mechanisms that can improve the benefit of radiotherapy in melanoma. It appears that BRAF intact cell lines are radiosensitive, whereas a mutation in at least one of the BRAF alleles at codon 600 leads to a radioresistant phenotype. We have adapted a pathway based targeting approach rather than the conventional gene based methods. We will present our preclinical studies on how genetic and molecular signatures in melanoma play a pivotal role in radiosensitizing melanoma and which subset of melanoma patients would derive the benefit from RT. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2504. doi:10.1158/1538-7445.AM2011-2504