Charles B. Simone

A moving target: Image guidance for stereotactic body radiation therapy for early-stage non-small cell lung cancer

PURPOSE Precise patient positioning is critical due to the large fractional doses and small treatment margins employed for thoracic stereotactic body radiation therapy (SBRT). The goals of this study were to evaluate the following: (1) the accuracy of kilovoltage x-ray (kV x-ray) matching to bony anatomy for pretreatment positioning; (2) the magnitude of intrafraction tumor motion; and (3) whether treatment or patient characteristics correlate with intrafraction motion. METHODS AND MATERIALS Eighty-seven patients with lung cancer were treated with SBRT. Patients were positioned with orthogonal kV x-rays matched to bony anatomy followed by cone-beam computed tomography (CBCT), with matching of the CBCT-visualized tumor to the internal gross target volume obtained from a 4-dimensional CT simulation data set. Patients underwent a posttreatment CBCT to assess the magnitude of intrafraction motion. RESULTS The mean CBCT-based shifts after initial patient positioning using kV x-rays were 2.2 mm in the vertical axis, 1.8 mm in the longitudinal axis, and 1.6 mm in the lateral axis (n = 335). The percentage of shifts greater than 3 mm and 5 mm represented 39% and 17%, respectively, of all fractions delivered. The mean CBCT-based shifts after treatment were 1.6 mm vertically, 1.5 mm longitudinally, and 1.1 mm laterally (n = 343). Twenty-seven percent and 10% of shifts were greater than 3 mm and 5 mm, respectively. Univariate and multivariable analysis demonstrated a significant association between intrafraction motion with weight and pulmonary function. CONCLUSIONS Kilovoltage x-ray matching to bony anatomy is inadequate for accurate positioning when a conventional 3-5 mm margin is employed prior to lung SBRT. Given the treatment techniques used in this study, CBCT image guidance with a 5-mm planning target volume margin is recommended. Further work is required to find determinants of interfraction and intrafraction motion that may help guide the individualized application of planning target volume margins.

Comparison of intensity-modulated radiotherapy, adaptive radiotherapy, proton radiotherapy, and adaptive proton radiotherapy for treatment of locally advanced head and neck cancer

BACKGROUND AND PURPOSE Various radiotherapy planning methods for locally advanced squamous cell carcinoma of the head and neck (SCCHN) have been proposed to decrease normal tissue toxicity. We compare IMRT, adaptive IMRT, proton therapy (IMPT), and adaptive IMPT for SCCHN. MATERIALS AND METHODS Initial and re-simulation CT images from 10 consecutive patients with SCCHN were used to quantify dosimetric differences between photon and proton therapy. Contouring was performed on both CTs, and plans (n=40 plans) and dose-volume histograms were generated. RESULTS The mean GTV volume decreased 53.4% with re-simulation. All plans provided comparable PTV coverage. Compared with IMRT, adaptive IMRT significantly reduced the maximum dose to the mandible (p=0.020) and mean doses to the contralateral parotid gland (p=0.049) and larynx (p=0.049). Compared with IMRT and adaptive IMRT, IMPT significantly lowered the maximum doses to the spinal cord (p<0.002 for both) and brainstem (p<0.002 for both) and mean doses to the larynx (p<0.002 for both) and ipsilateral (p=0.004 IMRT, p=0.050 adaptive) and contralateral (p<0.002 IMRT, p=0.010 adaptive) parotid glands. Adaptive IMPT significantly reduced doses to all critical structures compared with IMRT and adaptive IMRT and several critical structures compared with non-adaptive IMPT. CONCLUSIONS Although adaptive IMRT reduced dose to several normal structures compared with standard IMRT, non-adaptive proton therapy had a more favorable dosimetric profile than IMRT or adaptive IMRT and may obviate the need for adaptive planning. Protons allowed significant sparing of the spinal cord, parotid glands, larynx, and brainstem and should be considered for SCCHN to decrease normal tissue toxicity while still providing optimal tumor coverage.

Stereotactic Body Radiation Therapy for Lung Cancer

Lung cancer remains the leading cause of death worldwide. Because many patients with non-small cell lung cancer are elderly and have multiple comorbid conditions, many with potentially curable disease are unfit to undergo definitive surgical resection. Stereotactic body radiation therapy (SBRT) is increasingly being used to treat patients with medically inoperable stage I non-small cell lung cancer. SBRT combines reproducible and accurate anatomic targeting with the delivery of a very high dose per fraction of radiation to a target. Planning and delivery of SBRT is a coordinated effort between the radiation oncology team and consulting services. Clinical outcomes, toxicity profiles, treatment delivery, and indications for SBRT are reviewed. Services currently billed during planning and treatment of SBRT are detailed. This article introduces to consulting specialists and subspecialists a new Current Procedural Terminology code that has been proposed to more accurately reflect work performed during SBRT by these consulting providers. This code is described, and its implications for patient care are discussed.

Photodynamic therapy for the treatment of non-small cell lung cancer.

Photodynamic therapy is increasingly being utilized to treat thoracic malignancies. For patients with early-stage non-small cell lung cancer, photodynamic therapy is primarily employed as an endobronchial therapy to definitely treat endobronchial, roentgenographically occult, or synchronous primary carcinomas. As definitive monotherapy, photodynamic therapy is most effective in treating bronchoscopically visible lung cancers ≤1 cm with no extracartilaginous invasion. For patients with advanced-stage non-small cell lung cancer, photodynamic therapy can be used to palliate obstructing endobronchial lesions, as a component of definitive multi-modality therapy, or to increase operability or reduce the extent of operation required. A review of the available medical literature detailing all published studies utilizing photodynamic therapy to treat at least 10 patients with non-small cell lung cancer is performed, and treatment recommendations and summaries for photodynamic therapy applications are described.

First Clinical Investigation of Cone Beam Computed Tomography and Deformable Registration for Adaptive Proton Therapy for Lung Cancer

PURPOSE An adaptive proton therapy workflow using cone beam computed tomography (CBCT) is proposed. It consists of an online evaluation of a fast range-corrected dose distribution based on a virtual CT (vCT) scan. This can be followed by more accurate offline dose recalculation on the vCT scan, which can trigger a rescan CT (rCT) for replanning. METHODS AND MATERIALS The workflow was tested retrospectively for 20 consecutive lung cancer patients. A diffeomorphic Morphon algorithm was used to generate the lung vCT by deforming the average planning CT onto the CBCT scan. An additional correction step was applied to account for anatomic modifications that cannot be modeled by deformation alone. A set of clinical indicators for replanning were generated according to the water equivalent thickness (WET) and dose statistics and compared with those obtained on the rCT scan. The fast dose approximation consisted of warping the initial planned dose onto the vCT scan according to the changes in WET. The potential under- and over-ranges were assessed as a variation in WET at the targets distal surface. RESULTS The range-corrected dose from the vCT scan reproduced clinical indicators similar to those of the rCT scan. The workflow performed well under different clinical scenarios, including atelectasis, lung reinflation, and different types of tumor response. Between the vCT and rCT scans, we found a difference in the measured 95% percentile of the over-range distribution of 3.4 ± 2.7 mm. The limitations of the technique consisted of inherent uncertainties in deformable registration and the drawbacks of CBCT imaging. The correction step was adequate when gross errors occurred but could not recover subtle anatomic or density changes in tumors with complex topology. CONCLUSIONS A proton therapy workflow based on CBCT provided clinical indicators similar to those using rCT for patients with lung cancer with considerable anatomic changes.

Fractionated radiation alters oncomir and tumor suppressor miRNAs in human prostate cancer cells.

We have previously demonstrated that prostate carcinoma cells exposed to fractionated radiation differentially expressed more genes compared to single-dose radiation. To understand the role of miRNA in regulation of radiation-induced gene expression, we analyzed miRNA expression in LNCaP, PC3 and DU145 prostate cancer cells treated with single-dose radiation and fractionated radiation by microarray. Selected miRNAs were studied in RWPE-1 normal prostate epithelial cells by RT-PCR. Fractionated radiation significantly altered more miRNAs as compared to single-dose radiation. Downregulation of oncomiR-17-92 cluster was observed only in the p53 positive LNCaP and RWPE-1 cells treated with single-dose radiation and fractionated radiation. Comparison of miRNA and mRNA data by IPA target filter analysis revealed an inverse correlation between miR-17-92 cluster and several targets including TP53INP1 in p53 signaling pathway. The base level expressions of these miRNAs were significantly different among the cell lines and did not predict the radiation outcome. Tumor suppressor miR-34a and let-7 miRNAs were upregulated by fractionated radiation in radiosensitive LNCaP (p53 positive) and PC3 (p53-null) cells indicating that radiation-induced miRNA expression may not be regulated by p53 alone. Our data support the potential for using fractionated radiation to induce molecular targets and radiation-induced miRNAs may have a significant role in predicting radiosensitivity.

Therapeutic hyperthermia: The old, the new, and the upcoming.

Hyperthermia has long been used for cancer treatment, either alone or in combination with chemotherapy, radiation therapy, or both. Its efficacy and versatility continue to be well demonstrated in randomized trials across a number of primary cancers, but barriers to its widespread adoption persist including effective delivery and verification systems. This article describes hyperthermia, details its biological mechanisms of action and immunological effects, and summarizes select preclinical data and key clinical trials combining hyperthermia with standard cancer treatments. Current challenges and emerging technologies that have the potential to make this translational therapy more accessible to a greater number of patients are also described.

Consensus Statement on Proton Therapy in Early-Stage and Locally Advanced Non-Small Cell Lung Cancer

Radiation dose escalation has been shown to improve local control and survival in patients with non-small cell lung cancer in some studies, but randomized data have not supported this premise, possibly owing to adverse effects. Because of the physical characteristics of the Bragg peak, proton therapy (PT) delivers minimal exit dose distal to the target volume, resulting in better sparing of normal tissues in comparison to photon-based radiation therapy. This is particularly important for lung cancer given the proximity of the lung, heart, esophagus, major airways, large blood vessels, and spinal cord. However, PT is associated with more uncertainty because of the finite range of the proton beam and motion for thoracic cancers. PT is more costly than traditional photon therapy but may reduce side effects and toxicity-related hospitalization, which has its own associated cost. The cost of PT is decreasing over time because of reduced prices for the building, machine, maintenance, and overhead, as well as newer, shorter treatment programs. PT is improving rapidly as more research is performed particularly with the implementation of 4-dimensional computed tomography-based motion management and intensity modulated PT. Given these controversies, there is much debate in the oncology community about which patients with lung cancer benefit significantly from PT. The Particle Therapy Co-operative Group (PTCOG) Thoracic Subcommittee task group intends to address the issues of PT indications, advantages and limitations, cost-effectiveness, technology improvement, clinical trials, and future research directions. This consensus report can be used to guide clinical practice and indications for PT, insurance approval, and clinical or translational research directions.

Fractionated Radiation Therapy Can Induce a Molecular Profile for Therapeutic Targeting

Abstract To examine the possibility of using fractionated radiation in a unique way with molecular targeted therapy, gene expression profiles of prostate carcinoma cells treated with 10 Gy radiation administered either as a single dose or as fractions of 2 Gy × 5 and 1 Gy × 10 were examined by microarray analysis. Compared to the single dose, the fractionated irradiation resulted in significant increases in differentially expressed genes in both cell lines, with more robust changes in PC3 cells than in DU145 cells. The differentially expressed genes (>twofold change; P < 0.05) were clustered and their ontological annotations evaluated. In PC3 cells genes regulating immune and stress response, cell cycle and apoptosis were significantly up-regulated by multifractionated radiation compared to single-dose radiation. Ingenuity Pathway Analysis (IPA) of the differentially expressed genes revealed that immune response and cardiovascular genes were in the top functional category in PC3 cells and cell-to-cell signaling in DU145 cells. RT-PCR analysis showed that a flexure point for gene expression occurred at the 6th–8th fraction and AKT inhibitor perifosine produced enhanced cell killing after 1 Gy × 8 fractionated radiation in PC3 and DU145 cells compared to single dose. This study suggests that fractionated radiation may be a uniquely exploitable, non-oncogene-addiction stress pathway for molecular therapeutic targeting.

PREDICTED RATES OF SECONDARY MALIGNANCIES FROM PROTON VERSUS PHOTON RADIATION THERAPY FOR STAGE I SEMINOMA

PURPOSE Photon radiotherapy has been the standard adjuvant treatment for stage I seminoma. Single-dose carboplatin therapy and observation have emerged as alternative options due to concerns for acute toxicities and secondary malignancies from radiation. In this institutional review board-approved study, we compared photon and proton radiotherapy for stage I seminoma and the predicted rates of excess secondary malignancies for both treatment modalities. METHODS AND MATERIAL Computed tomography images from 10 consecutive patients with stage I seminoma were used to quantify dosimetric differences between photon and proton therapies. Structures reported to be at increased risk for secondary malignancies and in-field critical structures were contoured. Reported models of organ-specific radiation-induced cancer incidence rates based on organ equivalent dose were used to determine the excess absolute risk of secondary malignancies. Calculated values were compared with tumor registry reports of excess secondary malignancies among testicular cancer survivors. RESULTS Photon and proton plans provided comparable target volume coverage. Proton plans delivered significantly lower mean doses to all examined normal tissues, except for the kidneys. The greatest absolute reduction in mean dose was observed for the stomach (119 cGy for proton plans vs. 768 cGy for photon plans; p < 0.0001). Significantly more excess secondary cancers per 10,000 patients/year were predicted for photon radiation than for proton radiation to the stomach (4.11; 95% confidence interval [CI], 3.22-5.01), large bowel (0.81; 95% CI, 0.39-1.01), and bladder (0.03; 95% CI, 0.01-0.58), while no difference was demonstrated for radiation to the pancreas (0.02; 95% CI, -0.01-0.06). CONCLUSIONS For patients with stage I seminoma, proton radiation therapy reduced the predicted secondary cancer risk compared with photon therapy. We predict a reduction of one additional secondary cancer for every 50 patients with a life expectancy of 40 years from the time of radiation treatment with protons instead of photons. Proton radiation therapy also allowed significant sparing of most critical structures examined and warrants further study for patients with seminoma, to decrease radiation-induced toxicity.