Predictors of Nodal and Metastatic Failure in Early Stage Non-small-cell Lung Cancer After Stereotactic Body Radiation Therapy.

INTRODUCTION/BACKGROUND: Many patients with early stage non-small-cell lung cancer (ES-NSCLC) undergoing stereotactic body radiation therapy (SBRT) develop metastases, which is associated with poor outcomes. We sought to identify factors predictive of metastases after lung SBRT and created a risk stratification tool. MATERIALS AND METHODS: We included 363 patients with ES-NSCLC who received SBRT; the median follow-up was 5.8 years. The following patient and tumor factors were retrospectively analyzed for their association with metastases (defined as nodal and/or distant failure): gender; age; lobe involved; centrality; previous NSCLC; smoking status; gross tumor volume (GTV); T-stage; histology; dose; minimum, maximum, and mean GTV dose; and parenchymal lung failure. A metastasis risk-score linear-model using beta coefficients from a multivariate Cox model was built. RESULTS: A total of 111 (27.3%) of 406 lesions metastasized. GTV and dose were significantly associated with metastases on univariate and multivariate Cox proportional hazards modeling (P < .001 and hazard ratio [HR], 1.02 per mL; P < .05 and HR, 0.99 per Gy, respectively). Histology, T-stage, centrality, lung parenchymal failures, and previous NSCLC were not associated with development of metastasis. A metastasis risk-score model using GTV and prescription dose was built: risk score = (0.01611 × GTV) - (0.00525 × dose [BED10]). Two risk-score cutoffs separating the cohort into low-, medium-, and high-risk subgroups were examined. The risk score identified significant differences in time to metastases between low-, medium-, and high-risk patients (P < .001), with 3-year estimates of 81.1%, 63.8%, and 38%, respectively. CONCLUSION: GTV and radiation dose are associated with time to metastasis and may be used to identify patients at higher risk of metastasis after lung SBRT.

Dosimetric impact of gastrointestinal air column in radiation treatment of pancreatic cancer.

OBJECTIVE: Dosimetric evaluation of air column in gastrointestinal (GI) structures in intensity modulated radiation therapy (IMRT) of pancreatic cancer. METHODS: Nine sequential patients were retrospectively chosen for dosimetric analysis of air column in the GI apparatus in pancreatic cancer using cone beam CT (CBCT). The four-dimensional CT (4DCT) was used for target and organs at risk (OARs) and non-coplanar IMRT was used for treatment. Once a week, these patients underwent CBCT for air filling, isocentre verification and dose calculations retrospectively. RESULTS: Abdominal air column variation was as great as ±80% between weekly CBCT and 4DCT. Even with such a large air column in the treatment path for pancreatic cancer, changes in anteroposterior dimension were minimal (2.8%). Using IMRT, variations in air column did not correlate dosimetrically with large changes in target volume. An average dosimetric deviation of mere -3.3% and a maximum of -5.5% was observed. CONCLUSION: CBCT revealed large air column in GI structures; however, its impact is minimal for target coverage. Because of the inherent advantage of segmentation in IMRT, where only a small fraction of a given beam passes through the air column, this technique might have an advantage over 3DCRT in treating upper GI malignancies where the daily air column can have significant impact. Advances in knowledge: Radiation treatment of pancreatic cancer has significant challenges due to positioning, imaging of soft tissues and variability of air column in bowels. The dosimetric impact of variable air column is retrospectively studied using CBCT. Even though, the volume of air column changes by ± 80%, its dosimetric impact in IMRT is minimum.

DMAPT inhibits NF-κB activity and increases sensitivity of prostate cancer cells to X-rays in vitro and in tumor xenografts in vivo.

Constitutive activation of the pro-survival transcription factor NF-κB has been associated with resistance to both chemotherapy and radiation therapy in many human cancers, including prostate cancer. Our lab and others have demonstrated that the natural product parthenolide can inhibit NF-κB activity and sensitize PC-3 prostate cancers cells to X-rays in vitro; however, parthenolide has poor bioavailability in vivo and therefore has little clinical utility in this regard. We show here that treatment of PC-3 and DU145 human prostate cancer cells with dimethylaminoparthenolide (DMAPT), a parthenolide derivative with increased bioavailability, inhibits constitutive and radiation-induced NF-κB binding activity and slows prostate cancer cell growth. We also show that DMAPT increases single and fractionated X-ray-induced killing of prostate cancer cells through inhibition of DNA double strand break repair and also that DMAPT-induced radiosensitization is, at least partially, dependent upon the alteration of intracellular thiol reduction-oxidation chemistry. Finally, we demonstrate that the treatment of PC-3 prostate tumor xenografts with oral DMAPT in addition to radiation therapy significantly decreases tumor growth and results in significantly smaller tumor volumes compared to xenografts treated with either DMAPT or radiation therapy alone, suggesting that DMAPT might have a potential clinical role as a radiosensitizing agent in the treatment of prostate cancer.

Reirradiation of Recurrent and Second Primary Head and Neck Cancer With Proton Therapy.

PURPOSE: To report the clinical outcomes of head and neck reirradiation with proton therapy. METHODS AND MATERIALS: From 2004 to 2014, 61 patients received curative-intent proton reirradiation, primarily for disease involving skull base structures, at a median of 23 months from the most recent previous course of radiation. Most had squamous cell (52.5%) or adenoid cystic (16.4%) carcinoma. Salvage surgery before reirradiation was undertaken in 47.5%. Gross residual disease was present in 70.5%. For patients with microscopic residual disease, the median dose of reirradiation was 66 Gy (relative biological effectiveness), and for gross disease was 70.2 Gy (relative biological effectiveness). Concurrent chemotherapy was given in 27.9%. RESULTS: The median follow-up time was 15.2 months and was 28.7 months for patients remaining alive. The 2-year overall survival estimate was 32.7%, and the median overall survival was 16.5 months. The 2-year cumulative incidence of local failure with death as a competing risk was 19.7%; regional nodal failure, 3.3%; and distant metastases, 38.3%. On multivariable analysis, Karnofsky performance status ≤70%, the presence of a gastrostomy tube before reirradiation, and an increasing number of previous courses of radiation therapy were associated with a greater hazard ratio for death. A cutaneous primary tumor, gross residual disease, increasing gross tumor volume, and a lower radiation dose were associated with a greater hazard ratio for local failure. Grade ≥3 toxicities were seen in 14.7% acutely and 24.6% in the late setting, including 3 treatment-related deaths. CONCLUSIONS: Reirradiation with proton therapy, with or without chemotherapy, provided reasonable locoregional disease control, toxicity profiles, and survival outcomes for an advanced-stage and heavily pretreated population. Additional data are needed to identify which patients are most likely to benefit from aggressive efforts to achieve local disease control and to evaluate the potential benefit of proton therapy relative to other modalities of reirradiation.

Role of belly board device in the age of intensity modulated radiotherapy for pelvic irradiation.

Small bowel dose often represents a limiting factor for radiation treatment of pelvic malignancies. To reduce small bowel toxicity, a belly board device (BBD) with a prone position is often recommended. Intensity modulated radiotherapy (IMRT) could reduce dose to small bowel based on the desired dose-volume constraints. We investigated the efficacy of BBD in conjunction with IMRT. A total of 11 consecutive patients with the diagnosis of rectal cancer, who were candidates for definitive therapy, were selected. Patients were immobilized with BBD in prone position for simulation and treatment. Supine position computed tomography (CT) data were either acquired at the same time or during a diagnostic scan, and if existed was used. Target volumes (TV) as well as organs at risk (OAR) were delineated in both studies. Three-dimensional conformal treatment (3DCRT) and IMRT plans were made for both scans. Thus for each patient, 4 plans were generated. Statistical analysis was conducted for maximum, minimum, and mean dose to each structure. When comparing the normalized mean Gross TV dose for the different plans, there was no statistical difference found between the planning types. There was a significant difference in small bowel sparing when using prone position on BBD comparing 3DCRT and IMRT plans, favoring IMRT with a 29.6% reduction in dose (p = 0.007). There was also a statistically significant difference in small bowel sparing when comparing supine position IMRT to prone-BBD IMRT favoring prone-BBD IMRT with a reduction of 30.3% (p = 0.002). For rectal cancer when small bowel could be a limiting factor, prone position using BBD along with IMRT provides the best sparing. We conclude that whenever a dose escalation in rectal cancer is desired where small bowel could be limiting factor, IMRT in conjunction with BBD should be selected.

Does Graded Prognostic Assessment outperform Recursive Partitioning Analysis in patients with moderate prognosis brain metastases?

AIM: To compare the clinical utility of the Recursive Partitioning Analysis (RPA) and Graded Prognostic Assessment (GPA) in predicting outcomes for moderate prognosis patients with brain metastases. METHODS & MATERIALS: We reviewed 101 whole brain radiotherapy cases. RPA and GPA were calculated. Overall survival was compared. RESULTS: Sixty-eight patients had moderate prognosis. RPA patient characteristics for increased death hazard were ≤10 WBRT fractions or no surgery/radiosurgery. GPA patients had increased death risk with no surgery/radiosurgery or lower Karnofsky Performance Status. CONCLUSION: The indices have similar predicted survival. Patients scored by RPA with longer radiation schedules had longer survival; patients scored by GPA did not. This indicates GPA is more clinically useful, leaving less room for subjective treatment choices.

Quantifying Proton Fields for Midline Brain Tumors: A Benefit/Cost Analysis of Planning Objectives.

PURPOSE: We sought to quantify the optimum number of beams by using a midline sagittal arrangement for midline brain tumors when considering the competing demands of a high degree of target conformation and maximizing reduction of nontarget brain dose. The volume of nontarget brain tissue receiving between 5 and 20 Gy (V5-V20) was selected to measure "low-dose bath" to normal brain. MATERIALS AND METHODS: An exploratory model was developed with 6 midline brain targets created by using spheres of 1-, 3-, and 5-cm diameters located in superficial and deep locations. For each, five 3-dimensional proton treatment plans with uniform beam scanning were generated by using 1 to 5 fields. Dose-volume histograms were analyzed to calculate conformation number and V5-V20. A benefit/cost analysis was performed to determine the marginal gain in conformation number and the marginal cost of V5-V20 for the addition of each field and hypothesize the optimum number of treatment fields. We tested our hypothesis by re-planning 10 actual patient tumors with the same technique to compare the averages of these 50 plans to our model. RESULTS: Our model and validation cohort demonstrated the largest marginal benefit in target conformation and the lowest marginal cost in normal brain V5-V20 with the addition of a second proton field. The addition of a third field resulted in a relative marginal benefit in target conformation of just 3.9% but a relative marginal cost in V5-V20 of 78.7%. Normal brain absolute V5-V20 increased in a nearly linear fashion with each additional field. CONCLUSIONS: When treating midline brain lesions with 3-dimensional proton therapy in an array of midline sagittal beams, our model suggests the most appropriate number of fields is 2. There was little marginal benefit in target conformation and increasing cost of normal brain dose when increasing the number of fields beyond this.

Proton Radiotherapy for Midline Central Nervous System Lesions: A Class Solution.

OBJECTIVE: Midline and central lesions of the brain requiring conventional radiotherapy (RT) present complex difficulties in dose avoidance to organs at risk (OAR). In either definitive or adjuvant settings, proper RT coverage of these lesions involves unnecessary treatment of large volumes of normal brain. We propose a class solution for these lesions using proton radiotherapy (PrT). MATERIALS AND METHODS: The records of the Indiana University Health Proton Therapy Center were reviewed for patients presenting between January 1, 2005 and October 1, 2013 with midline central nervous system (CNS) lesions. Twenty-four patients were identified. After Institutional Review Board approval was granted, their dosimetry was reviewed for target volume doses and OAR dose avoidance. RESULTS: For these cases, meningiomas were the most common histology (8 cases), and next most prevalent were craniopharyngiomas (6 cases). The others were various different deep midline brain tumors (10 cases). In all cases, fields formed by vertex and/or anterior/posterior superior oblique PrT beams along the midsagittal plane were used to provide coverage with minimal dose to the brain stem or to the cerebral hemispheres. The median prescribed dose to the planning target volume for treating these patients was 54.0 Gy RBE (range 48.6-62.5) with a mean dose of 53.5 Gy RBE. The average of the mean doses to the brain stems using these fields in the 24 plans was 18.4 Gy RBE (range 0.0-44.7). Similarly, the average of the mean doses to the hippocampi was 15.8 Gy RBE (range 0.0-52.6). CONCLUSIONS: We consider these patients to be optimally treated with PrT. The use of modified midsagittal PrT schemas allows for the treatment of midline CNS lesions with sparing of most of the uninvolved brain.

Effect of Scanning Beam for Superficial Dose in Proton Therapy.

Proton beam delivery technology is under development to minimize the scanning spot size for uniform dose to target, but it is also known that the superficial dose could be as high as the dose at Bragg peak for narrow and small proton beams. The objective of this study is to explore the characteristics of dose distribution at shallow depths using Monte Carlo simulation with the FLUKA code for uniform scanning (US) and discrete spot scanning (DSS) proton beams. The results show that the superficial dose for DSS is relatively high compared to US. Additionally, DSS delivers a highly heterogeneous dose to the irradiated surface for comparable doses at Bragg peak. Our simulation shows that the superficial dose can become as high as the Bragg peak when the diameter of the proton beam is reduced. This may compromise the advantage of proton beam therapy for sparing normal tissue, making skin dose a limiting factor for the clinical use of DSS. Finally, the clinical advantage of DSS may not be essential for treating uniform dose across a large target, as in craniospinal irradiation (CSI).

Whole brain radiotherapy for poor prognosis patients with brain metastases: predictably poor results.

BACKGROUND: Patients with brain metastases from solid tumors can be subdivided by characteristics into separate prognostic groups, such as the Radiation Therapy Oncology Group's Recursive Partitioning Analysis (RPA) or the Graded Prognostic Assessment (GPA). At our institution, patients falling into the poorest prognostic groups are often treated with whole brain radiotherapy (WBRT). OBJECTIVE: To determine if observed survival of poor prognosis patients treated with WBRT for brain metastases at our institution matches the survival predicted by RPA and GPA prognostic indices. METHODS: The charts of 101 consecutive patients with newly diagnosed brain metastases from solid tumors who received WBRT were retrospectively reviewed. We calculated each patient's RPA and GPA and compiled treatment and survival data. Observed median survival was compared to that predicted by the RPA and GPA prognostic indices. RESULTS: RPA III patients (n = 25) had a median survival of 2.4 months in our study. GPA 0.0-1.0 patients (n = 35) had a median survival of 2.4 months in our study. These values did not vary significantly from those predicted by the respective indices. LIMITATIONS: This is a retrospective analysis and subject to selection bias. CONCLUSION: Given the delivery time for WBRT and the potential side effects associated with the treatment, the predictably short overall survival in poor prognosis patients calls into question the value of WBRT in this patient subgroup.

Inhibition of NF-κB and DNA double-strand break repair by DMAPT sensitizes non-small-cell lung cancers to X-rays.

We investigated the efficacy and mechanism of dimethylaminoparthenolide (DMAPT), an NF-κB inhibitor, to sensitize human lung cancer cells to X-ray killing in vitro and in vivo. We tested whether DMAPT increased the effectiveness of single and fractionated X-ray treatment through inhibition of NF-κB and/or DNA double-strand break (DSB) repair. Treatment with DMAPT decreased plating efficiency, inhibited constitutive and radiation-induced NF-κB binding activity, and enhanced radiation-induced cell killing by dose modification factors of 1.8 and 1.4 in vitro. X-ray fractionation demonstrated that DMAPT inhibited split-dose recovery/repair, and neutral DNA comet assays confirmed that DMAPT altered the fast and slow components of X-ray-induced DNA DSB repair. Knockdown of the NF-κB family member p65 by siRNA increased radiation sensitivity and completely inhibited split-dose recovery in a manner very similar to DMAPT treatment. The data suggest a link between inhibition of NF-κB and inhibition of DSB repair by DMAPT that leads to enhancement of X-ray-induced cell killing in vitro in non-small-cell lung cancer cells. Studies of A549 tumor xenografts in nude mice demonstrated that DMAPT enhanced X-ray-induced tumor growth delay in vivo.