Integrating Mathematical Modeling into the Roadmap for Personalized Adaptive Radiation Therapy

In current radiation oncology practice, treatment protocols are prescribed based on the average outcomes of large clinical trials, with limited personalization and without adaptations of dose or dose fractionation to individual patients based on their individual clinical responses. Predicting tumor responses to radiation and comparing predictions against observed responses offers an opportunity for novel treatment evaluation. These analyses can lead to protocol adaptation aimed at the improvement of patient outcomes with better therapeutic ratios. We foresee the integration of mathematical models into radiation oncology to simulate individual patient tumor growth and predict treatment response as dynamic biomarkers for personalized adaptive radiation therapy (RT)

Imatinib mesylate (gleevec)--targeted kinases are expressed in uterine sarcomas

The purpose of this study was to determine whether 3 tyrosine kinases known to be inhibited by imatinib mesylate are expressed in a variety of uterine sarcomas. The authors assessed c-kit, abl, and platelet-derived growth factor receptor-beta (PDGFR-beta) expression in 8 endometrial stromal sarcomas (ESSs), 5 leiomyosarcomas (LMSs), 4 high-grade endometrial sarcomas (HGESs), and 21 malignant mixed mullerian tumors (MMMTs). Tissue sections were stained with commercially available antibodies for c-kit, abl, and PDGFR-beta. Staining intensity was described as 0 (no staining), +1 (weak), +2 (moderate), and +3 (strong). Positive staining was defined as moderate to strong if found in more than 10% of tumor cells. Expression of c-kit ranged from 0% in LMSs to 25% in HGESs. Protein expression of abl was more significant, ranging from 25% in LMSs and ESSs to 43% in MMMTs. Only 1 LMS sample stained focally for abl (+1). Abl expression was observed in only the carcinomatous elements of the MMMTs, with diffuse staining in the cytoplasm and nucleus. In most, the staining intensity was +2. All tumors stained positive for PDGFR-beta. MMMT samples showed PDGFR-beta expression in both the carcinomatous and sarcomatous portions. In all samples, staining for PDGFR-beta was concentrated at the cell membrane and diffusely in the cytoplasm. These results indicate that many uterine sarcomas express 1 or more of the kinases targeted by imatinib mesylate and that further investigation of imatinib as a therapy for uterine sarcomas is warranted

Temporally feathered intensity-modulated radiation therapy: A planning technique to reduce normal tissue toxicity.

Purpose: Intensity-modulated radiation therapy (IMRT) has allowed optimization of three-dimensional spatial radiation dose distributions permitting target coverage while reducing normal tissue toxicity. However, radiation-induced normal tissue toxicity is a major contributor to patients' quality of life and often a dose-limiting factor in the definitive treatment of cancer with radiation therapy. We propose the next logical step in the evolution of IMRT using canonical radiobiological principles, optimizing the temporal dimension through which radiation therapy is delivered to further reduce radiation-induced toxicity by increased time for normal tissue recovery. We term this novel treatment planning strategy "temporally feathered radiation therapy" (TFRT). Methods: Temporally feathered radiotherapy plans were generated as a composite of five simulated treatment plans each with altered constraints on particular hypothetical organs at risk (OARs) to be delivered sequentially. For each of these TFRT plans, OARs chosen for feathering receive higher doses while the remaining OARs receive lower doses than the standard fractional dose delivered in a conventional fractionated IMRT plan. Each TFRT plan is delivered a specific weekday, which in effect leads to a higher dose once weekly followed by four lower fractional doses to each temporally feathered OAR. We compared normal tissue toxicity between TFRT and conventional fractionated IMRT plans by using a dynamical mathematical model to describe radiation-induced tissue damage and repair over time. Results: Model-based simulations of TFRT demonstrated potential for reduced normal tissue toxicity compared to conventionally planned IMRT. The sequencing of high and low fractional doses delivered to OARs by TFRT plans suggested increased normal tissue recovery, and hence less overall radiation-induced toxicity, despite higher total doses delivered to OARs compared to conventional fractionated IMRT plans. The magnitude of toxicity reduction by TFRT planning was found to depend on the corresponding standard fractional dose of IMRT and organ-specific recovery rate of sublethal radiation-induced damage. Conclusions: TFRT is a novel technique for treatment planning and optimization of therapeutic radiotherapy that considers the nonlinear aspects of normal tissue repair to optimize toxicity profiles. Model-based simulations of TFRT to carefully conceptualized clinical cases have demonstrated potential for radiation-induced toxicity reduction in a previously described dynamical model of normal tissue complication probability (NTCP)

Gastrostomy tube placement and use in patients with head and neck cancer

BACKGROUND: Enteral nutritional support is used in care for patients with head and neck cancer. This study describes the frequency and timing of gastrostomy tube placement and corresponding Medicare nutritional support claims in patients with head and neck cancer. METHODS: Surveillance, Epidemiology, and End Results (SEER)-Medicare data for patients with head and neck cancer diagnosed from 2000 to 2005 were used in this descriptive study (N = 16,458). RESULTS: In all, 35.1% of patients undergoing treatment had gastrostomy tubes placed; 16.9% had tubes placed before treatment, whereas 83.1% had them placed after treatment. Of those having tubes placed prior to treatment 23.7% had Medicare claims for nutritional support before treatment and 40.9% had claims after treatment began. A total of 35.4% of patients who had tubes placed before treatment and 35.5% who had tubes placed after treatment had no claims for nutritional support. CONCLUSIONS: Future work is warranted to identify predictors and outcomes associated with provision and timing of enteral nutrition support for patients with head and neck cancer

Patterns of prophylactic gastrostomy tube placement in head and neck cancer patients: A consideration of the significance of social support and practice variation

OBJECTIVES/HYPOTHESIS: The purpose of this study was to examine factors associated with prophylactic placement of feeding tubes in head and neck cancer patients receiving radiation therapy as a part of treatment using multilevel models that account for patient-, physician-, and institution-level sources of variation. STUDY DESIGN: A retrospective analysis using binary logistic regression and hierarchical linear models was run to evaluate independent predictors of prophylactic feeding tube placement. METHODS: Surveillance, Epidemiology, and End Results-Medicare data were used. Head and neck cancer patients diagnosed with locoregionally advanced stage disease from 2000 to 2005 were included in this study (N = 8,306). RESULTS: Across all models, prophylactic gastrostomy tube placement was found to be more likely in patients who had cancer of the larynx or oropharynx compared with those with cancer of the nasopharynx or oral cavity; who had regional instead of local cancer; who did not receive surgery as a part of treatment, but did receive chemotherapy; and who were divorced, separated, or widowed. Additionally, although practice variation was observed to occur, its overall contribution in predicting prophylactic gastrostomy tube placement was minimal. CONCLUSIONS: As health care enters an era of patient-centered care, further investigation of the potential role of social support (or lack of social support) in influencing treatment decisions of head and neck cancer patients and providers is warranted. LEVEL OF EVIDENCE: 2b Laryngoscope, 2013. Society, Inc

Patterns of prophylactic gastrostomy tube placement in head and neck cancer patients: a consideration of the significance of social support and practice variation.

Objectives/hypothesisThe purpose of this study was to examine factors associated with prophylactic placement of feeding tubes in head and neck cancer patients receiving radiation therapy as a part of treatment using multilevel models that account for patient-, physician-, and institution-level sources of variation.Study designA retrospective analysis using binary logistic regression and hierarchical linear models was run to evaluate independent predictors of prophylactic feeding tube placement.MethodsSurveillance, Epidemiology, and End Results-Medicare data were used. Head and neck cancer patients diagnosed with locoregionally advanced stage disease from 2000 to 2005 were included in this study (N = 8,306).ResultsAcross all models, prophylactic gastrostomy tube placement was found to be more likely in patients who had cancer of the larynx or oropharynx compared with those with cancer of the nasopharynx or oral cavity; who had regional instead of local cancer; who did not receive surgery as a part of treatment, but did receive chemotherapy; and who were divorced, separated, or widowed. Additionally, although practice variation was observed to occur, its overall contribution in predicting prophylactic gastrostomy tube placement was minimal.ConclusionsAs health care enters an era of patient-centered care, further investigation of the potential role of social support (or lack of social support) in influencing treatment decisions of head and neck cancer patients and providers is warranted