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1.  Stereotactic ablative radiotherapy: aim for a cure of cancer 
doi:10.3978/j.issn.2305-5839.2014.11.17
PMCID: PMC4293479
2.  Therapy resistant cancer stem cells have differing sensitivity to photon versus proton beam radiation 
Background
Cancer stem cells (CSCs) play an important role in non–small cell lung cancer (NSCLC) recurrence and metastasis. We sought to determine whether CSC-like cells respond differentially to proton and photon beam therapies.
Materials and methods
CSC-enriched cells from paclitaxel-resistant human H460 and A549 cell lines were irradiated with the same relative biological effectiveness dose and analyzed for cell viability, clonogenic survival, apoptosis, cell migration, cell invasiveness, tumor sphere formation, and CSC markers. The intracellular concentration of reactive oxygen species (ROS) was measured before and after irradiation.
Results
Compared with photons, protons caused significantly lower cell viability in chemoresistant cells and, in CSC-like cells, significantly lower clonogenic survival, invasiveness, and number of tumor spheres; less migration and CSC markers (CAR, β-catenin, and side population cells); more apoptosis; and higher ROS level. CSC-like cells contained less than half the ROS levels of parental cancer cells or normal human bronchial epithelial cells.
Conclusions
CSC-like cells may be more sensitive to irradiation with protons than photons. The increased sensitivity could be caused by the greater ROS generated by protons. Because chemoresistant CSCs play an important role in tumor recurrence, protons may be more effective than photons in eliminating recurrent or persistent NSCLC.
doi:10.1097/JTO.0b013e3182a5fdcb
PMCID: PMC3882687  PMID: 24389430
NSCLC; cancer stem cells; treatment resistance; proton therapy; photon therapy
3.  Stereotactic Ablative Radiotherapy: A Potentially Curable Approach to Early-Stage Multiple Primary Lung Cancer 
Cancer  2013;119(18):3402-3410.
BACKGROUND
Surgical resection has been the standard treatment for early-stage multiple primary lung cancer (MPLC). However, a significant proportion of patients with MPLC cannot undergo surgery. We explored here the role of stereotactic ablative radiotherapy (SABR) for patients with MPLC.
METHODS
We reviewed MPLC cases treated with SABR (50 Gy in 4 fractions or 70 Gy in 10 fractions) for the second tumor. Four-dimensional CT–based planning/volumetric image-guided treatment was used for all patients. Treatment outcomes/toxicities were analyzed.
RESULTS
For the 101 patients treated with SABR, at a median follow-up interval of 36 months and median overall survival of 46 months, 2-year and 4-year in-field local control rates were 97.4% and 95.7%. 2- and 4-year rates of overall survival (OS) were 73.2% and 47.5% and progression-free survival (PFS) were 67.0% and 58.0%. Patients with metachronous tumors had higher OS and PFS than did patients with synchronous tumors (2-year OS 80.6% metachronous vs. 61.5% synchronous; 4-year OS 52.7% vs. 39.7%; p=0.047; 2-year PFS 84.7% vs. 49.4%; 4-year PFS 75.6% vs. 30.4%; p=0.0001). For patients whose index tumor was treated with surgery or SABR, the incidence of grade ≥3 radiation pneumonitis was 3% (2/71), but this increased to 17% (5/30) for patients whose index tumor was treated with conventional radiotherapy. Other grade ≥3 toxicities included grade 3 chest wall pain (3/101, 3%) and grade 3 skin toxicity (1/101, 1%).
CONCLUSIONS
SABR achieves promising long- term tumor control, survival and could be a potential curative treatment of early-stage MPLC.
doi:10.1002/cncr.28217
PMCID: PMC3775964  PMID: 23798353
multiple primary lung cancer; synchronous tumors; metachronous tumors; stereotactic body radiotherapy; stereotactic ablative radiotherapy
4.  Proton-Based Stereotactic Ablative Radiotherapy in Early-Stage Non-Small-Cell Lung Cancer 
BioMed Research International  2014;2014:389048.
Stereotactic ablative radiotherapy (SABR), a recent implementation in the practice of radiation oncology, has been shown to confer high rates of local control in the treatment of early stage non-small-cell lung cancer (NSCLC). This technique, which involves limited invasive procedures and reduced treatment intervals, offers definitive treatment for patients unable or unwilling to undergo an operation. The use of protons in SABR delivery confers the added physical advantage of normal tissue sparing due to the absence of collateral radiation dose delivered to regions distal to the target. This may translate into clinical benefit and a decreased risk of clinical toxicity in patients with nearby critical structures or limited pulmonary reserve. In this review, we present the rationale for proton-based SABR, principles relating to the delivery and planning of this modality, and a summary of published clinical studies.
doi:10.1155/2014/389048
PMCID: PMC4124720  PMID: 25136582
5.  Adaptive Radiation for Lung Cancer 
Journal of Oncology  2010;2011:898391.
The challenges of lung cancer radiotherapy are intra/inter-fraction tumor/organ anatomy/motion changes and the need to spare surrounding critical structures. Evolving radiotherapy technologies, such as four-dimensional (4D) image-based motion management, daily on-board imaging and adaptive radiotherapy based on volumetric images over the course of radiotherapy, have enabled us to deliver higher dose to target while minimizing normal tissue toxicities. The image-guided radiotherapy adapted to changes of motion and anatomy has made the radiotherapy more precise and allowed ablative dose delivered to the target using novel treatment approaches such as intensity-modulated radiation therapy, stereotactic body radiation therapy, and proton therapy in lung cancer, techniques used to be considered very sensitive to motion change. Future clinical trials using real time tracking and biological adaptive radiotherapy based on functional images are proposed.
doi:10.1155/2011/898391
PMCID: PMC2931378  PMID: 20814539
6.  Phase II Trial of Erlotinib Plus Concurrent Whole-Brain Radiation Therapy for Patients With Brain Metastases From Non–Small-Cell Lung Cancer 
Journal of Clinical Oncology  2013;31(7):895-902.
Purpose
Brain metastasis (BM) is a leading cause of death from non–small-cell lung cancer (NSCLC). Reasoning that activation of the epidermal growth factor receptor (EGFR) contributes to radiation resistance, we undertook a phase II trial of the EGFR inhibitor erlotinib with whole-brain radiation therapy (WBRT) in an attempt to extend survival time for patients with BM from NSCLC. Additional end points were radiologic response and safety.
Patients and Methods
Eligible patients had BM from NSCLC, regardless of EGFR status. Erlotinib was given at 150 mg orally once per day for 1 week, then concurrently with WBRT (2.5 Gy per day 5 days per week, to 35 Gy), followed by maintenance. EGFR mutation status was tested by DNA sequencing at an accredited core facility.
Results
Forty patients were enrolled and completed erlotinib plus WBRT (median age, 59 years; median diagnosis-specific graded prognostic assessment score, 1.5). The overall response rate was 86% (n = 36). No increase in neurotoxicity was detected, and no patient experienced grade ≥ 4 toxicity, but three patients required dose reduction for grade 3 rash. At a median follow-up of 28.5 months (for living patients), median survival time was 11.8 months (95% CI, 7.4 to 19.1 months). Of 17 patients with known EGFR status, median survival time was 9.3 months for those with wild-type EGFR and 19.1 months for those with EGFR mutations.
Conclusion
Erlotinib was well tolerated in combination with WBRT, with a favorable objective response rate. The higher-than-expected rate of EGFR mutations in these unselected patients raises the possibility that EGFR-mutated tumors are prone to brain dissemination.
doi:10.1200/JCO.2011.40.1174
PMCID: PMC3577951  PMID: 23341526
7.  Coxsackie- and adenovirus receptor as a novel marker of stem cells in treatment-resistant non-small cell lung cancer 
Background
Treatment resistance resulting from the presence of cancer stem cells (CSCs) remains a challenge in cancer treatment. Little is known about possible markers of CSCs in treatment-resistant non-small cell lung cancer (NSCLC). We explored the coxsackie- and adenovirus receptor (CAR) as one such marker of CSCs in models of treatment-resistant NSCLC.
Materials and methods
Resistant H460 and A549 cell lines were established by repeated exposure to paclitaxel or fractionated radiation. CSC markers were measured by western blotting and flow cytometry. We also established stable CAR-overexpressing and stable shRNA-CAR-knockdown cell lines and assessed their survival, invasiveness, and tumorigenic capabilities with clonogenic, telomerase, Matrigel, and tumor formation assays.
Results
CAR expression was associated with CSC phenotype both in vitro and in vivo. CAR-overexpressing cells were more treatment-resistant, self-renewing, and tumorigenic than were parental cells, and shRNA-mediated knockdown of CAR expression was sufficient to inhibit these functions. CAR expression also correlated with the epithelial-mesenchymal transition.
Conclusions
We showed for the first time that CAR is a marker of CSCs and may affect the activities of CSCs in treatment-resistant NSCLC. CAR may prove to be a target for CSC treatment and a predictor of treatment response in patients with NSCLC.
doi:10.1016/j.radonc.2012.09.002
PMCID: PMC3845342  PMID: 23022172
Coxsackie-adenovirus receptor; treatment resistance; NSCLC; cancer stem cells; molecular markers
8.  Adaptive/non-adaptive proton radiation planning and outcome in a phase II trial for locally advanced non-small cell lung cancer 
Purpose
To analyze dosimetric variables and outcomes after adaptive replanning of radiotherapy during concurrent high-dose protons and chemotherapy for locally advanced non-small cell lung cancer (NSCLC).
Methods and Materials
Nine of 44 patients with stage III NSCLC in a prospective phase II trial of concurrent paclitaxel/carboplatin with proton radiation [74 Gy(RBE) in 37 fractions] had modifications to their original treatment plans after re-evaluation revealed changes that would compromise coverage of the target volume or violate dose constraints; plans for the other 35 patients were not changed. We compared patients with adaptive plans with those with nonadaptive plans in terms of dosimetry and outcomes.
Results
At a median follow-up of 21.2 months (median overall survival, 29.6 months), no differences were found in local, regional, or distant failure or overall survival between groups. Adaptive planning was used more often for large tumors that shrank to a greater extent (median, 107.1 cm3 adaptive and 86.4 cm3 non-adaptive; median changes in volume, 25.3% adaptive and 1.2% non-adaptive; p<0.01). The median number of fractions delivered using adaptive planning was 13 (range, 4–22). Adaptive planning generally improved sparing of the esophagus (median absolute decrease in V70, 1.8%; range, 0–22.9%) and spinal cord (median absolute change in maximum dose, 3.7 Gy; range, 0–13.8 Gy). Without adaptive replanning, target coverage would have been compromised in 2 cases (57% and 82% coverage without adaptation vs. 100% for both with adaptation); neither patient experienced local failure. Radiation-related grade 3 toxicity rates were similar between groups.
Conclusions
Adaptive planning can reduce normal tissue doses and prevent target misses, particularly for patients with large tumors that shrink substantially during therapy. Adaptive plans seem to have acceptable toxicity and achieve similar local, regional, and distant control and overall survival, even in patients with larger tumors, versus non-adaptive plans.
doi:10.1016/j.ijrobp.2012.02.041
PMCID: PMC3409930  PMID: 22543217
proton radiation; adaptive planning; non-small cell lung cancer; image-guided radiation therapy; chemoradiation
9.  Predicting Radiation Pneumonitis After Stereotactic Ablative Radiation Therapy in Patients Previously Treated With Conventional Thoracic Radiation Therapy 
Purpose
To determine the incidence of and risk factors for radiation pneumonitis (RP) after stereotactic ablative radiation therapy (SABR) to the lung in patients who had previously undergone conventional thoracic radiation therapy.
Methods and Materials
Seventy-two patients who had previously received conventionally fractionated radiation therapy to the thorax were treated with SABR (50 Gy in 4 fractions) for recurrent disease or secondary parenchymal lung cancer (T <4 cm, N0, M0, or Mx). Severe (grade ≥3) RP and potential predictive factors were analyzed by univariate and multivariate logistic regression analyses. A scoring system was established to predict the risk of RP.
Results
At a median follow-up time of 16 months after SABR (range, 4-56 months), 15 patients had severe RP (14 [18.9%] grade 3 and 1 [1.4%] grade 5) and 1 patient (1.4%) had a local recurrence. In univariate analyses, Eastern Cooperative Oncology Group performance status (ECOG PS) before SABR, forced expiratory volume in 1 second (FEV1), and previous planning target volume (PTV) location were associated with the incidence of severe RP. The V10 and mean lung dose (MLD) of the previous plan and the V10-V40 and MLD of the composite plan were also related to RP. Multivariate analysis revealed that ECOG PS scores of 2-3 before SABR (P=.009), FEV1 ≤65% before SABR (P=.012), V20 ≥30% of the composite plan (P=.021), and an initial PTV in the bilateral mediastinum (P=.025) were all associated with RP.
Conclusions
We found that severe RP was relatively common, occurring in 20.8% of patients, and could be predicted by an ECOG PS score of 2-3, an FEV1 ≤ 65%, a previous PTV spanning the bilateral mediastinum, and V20 ≥30% on composite (previous RT + SABR) plans. Prospective studies are needed to validate these predictors and the scoring system on which they are based.
doi:10.1016/j.ijrobp.2012.02.020
PMCID: PMC3612879  PMID: 22543216
10.  Oligometastases/Oligo-Recurrence of Lung Cancer 
Pulmonary Medicine  2013;2013:438236.
doi:10.1155/2013/438236
PMCID: PMC3586482  PMID: 23476762
11.  Positron Emission Tomography for Assessing Local Failure After Stereotactic Body Radiotherapy for Non-Small-Cell Lung Cancer 
Purpose
We analyzed whether positron emission tomography (PET)/computed tomography standardized uptake values (SUVs) after stereotactic body radiotherapy (SBRT) could predict local recurrence (LR) in non-small-cell lung cancer (NSCLC).
Methods and Materials
This study comprised 128 patients with Stage I (n = 68) or isolated recurrent/secondary parenchymal (n = 60) NSCLC treated with image-guided SBRT to 50 Gy over 4 consecutive days; prior radiotherapy was allowed. PET/computed tomography scans were obtained before therapy and at 1 to 6 months after therapy, as well as subsequently as clinically indicated. Continuous variables were analyzed with Kruskal-Wallis tests and categorical variables with Pearson chi-square or Fisher exact tests. Actuarial local failure rates were calculated with the Kaplan-Meier method.
Results
At a median follow-up of 31 months (range, 6–71 months), the actuarial 1-, 2-, and 3-year local control rates were 100%, 98.5%, and 98.5%, respectively, in the Stage I group and 95.8%, 87.6%, and 85.8%, respectively, in the recurrent group. The cumulative rates of regional nodal recurrence and distant metastasis were 8.8% (6 of 68) and 14.7% (10 of 68), respectively, for the Stage I group and 11.7% (7 of 60) and 16.7% (10 of 60), respectively, for the recurrent group. Univariate analysis showed that SUVs obtained 12.1 to 24 months after treatment for the Stage I group (p = 0.007) and 6.1 to 12 months and 12.1 to 24 months after treatment for the recurrent group were associated with LR (p < 0.001 for both). Of the 128 patients, 17 (13.3%) had ipsilateral consolidation after SBRT but no elevated metabolic activity on PET; none had LR. The cutoff maximum SUV of 5 was found to have 100% sensitivity, 91% specificity, a 50% positive predictive value, and a 100% negative predictive value for predicting LR.
Conclusions
PET was helpful for distinguishing SBRT-induced consolidation from LR. SUVs obtained more than 6 months after SBRT for NSCLC were associated with local failure.
doi:10.1016/j.ijrobp.2011.10.035
PMCID: PMC3474601  PMID: 22572078
Stereotactic body radiotherapy; Non-small-cell lung cancer; 18F-fluorodeoxyglucose positron emission tomography; Local recurrence
12.  Phase II Study of High-Dose Proton Therapy with Concurrent Chemotherapy for Unresectable Stage III Non-Small Cell Lung Cancer 
Cancer  2011;117(20):4707-4713.
BACKGROUND
We sought here to improve the toxicity of conventional concurrent chemoradiation therapy for stage III non-small cell lung cancer (NSCLC) by using proton-beam therapy to escalate the radiation dose to the tumor. We report early results of a phase II study of high-dose proton therapy and concurrent chemotherapy in terms of toxicity, failure patterns, and survival.
METHODS
Forty-four patients with stage III NSCLC were treated with 74 Gy(RBE) proton therapy with weekly carboplatin (AUC 2) and paclitaxel (50 mg/m2). Disease was staged with positron emission tomography/computed tomography (PET/CT) and treatments simulated with 4-dimensional CT to account for tumor motion. Protons were delivered as passively scattered beams, and treatment simulation was repeated during the treatment process to determine the need for adaptive re-planning.
RESULTS
Median follow-up time was 19.7 months (range, 6.1–44.4 months) and median overall survival time was 29.4 months. . No patient experienced grade 4 or 5 proton-related adverse events. The most common nonhematologic grade 3 toxicities were dermatitis (n=5), esophagitis (n=5), and pneumonitis (n=1). Nine patients (20.5%) experienced local disease recurrence but only four (9.1%) had isolated local failure. Four patients (9.1%) had regional lymph node recurrence but only one (2.3%) had isolated regional recurrence. Nineteen patients (43.2%) developed distant metastasis. The overall survival and progression-free survival rates were 86% and 63% at 1 year.
CONCLUSIONS
Concurrent high-dose proton and chemotherapy is well tolerated, and the median survival time of 29.4 months is encouraging for unresectable stage III NSCLC.
doi:10.1002/cncr.26080
PMCID: PMC3174272  PMID: 21437893
Proton therapy; concurrent chemotherapy; non-small cell lung cancer; toxicity; patterns of failure; survival
13.  POSITRON EMISSION TOMOGRAPHY/COMPUTED TOMOGRAPHY-GUIDED INTENSITY-MODULATED RADIOTHERAPY FOR LIMITED-STAGE SMALL-CELL LUNG CANCER 
Purpose
Omitting elective nodal irradiation from planning target volumes does not compromise outcomes in patients with non–small-cell lung cancer, but whether the same is true for those with limited-stage small-cell lung cancer (LS-SCLC) is unknown. Therefore, in the present study, we sought to determine the clinical outcomes and the frequency of elective nodal failure in patients with LS-SCLC staged using positron emission tomography/computed tomography and treated with involved-field intensity-modulated radiotherapy.
Methods and Materials
Between 2005 and 2008, 60 patients with LS-SCLC at our institution underwent disease staging using positron emission tomography/computed tomography before treatment using an intensity-modulated radiotherapy plan in which elective nodal irradiation was intentionally omitted from the planning target volume (mode and median dose, 45 Gy in 30 fractions; range, 40.5 Gy in 27 fractions to 63.8 Gy in 35 fractions). In most cases, concurrent platinum-based chemotherapy was administered. We retrospectively reviewed the clinical outcomes to determine the overall survival, relapse-free survival, and failure patterns. Elective nodal failure was defined as recurrence in initially uninvolved hilar, mediastinal, or supraclavicular nodes. Survival was assessed using the Kaplan-Meier method.
Results
The median age of the study patients at diagnosis was 63 years (range, 39–86). The median follow-up duration was 21 months (range, 4–58) in all patients and 26 months (range, 4–58) in the survivors. The 2-year actuarial overall survival and relapse-free survival rate were 58% and 43%, respectively. Of the 30 patients with recurrence, 23 had metastatic disease and 7 had locoregional failure. We observed only one isolated elective nodal failure.
Conclusions
To our knowledge, this is the first study to examine the outcomes in patients with LS-SCLC staged with positron emission tomography/computed tomography and treated with definitive intensity-modulated radiotherapy. In these patients, elective nodal irradiation can be safely omitted from the planning target volume for the purposes of dose escalation and toxicity reduction.
doi:10.1016/j.ijrobp.2010.12.072
PMCID: PMC3465842  PMID: 21489716
Small-cell lung cancer; Involved field radiation; Positron emission tomography; PET; Intensity-modulated radiotherapy; IMRT
14.  Toxicity and Patterns of Failure of Adaptive/Ablative Proton Therapy for Early-Stage, Medically Inoperable Non-Small Cell Lung Cancer 
Purpose
To analyze the toxicity and patterns of failure of proton therapy given in ablative doses for medically inoperable early-stage non-small cell lung cancer (NSCLC).
Methods and Materials
Eighteen patients with medically inoperable T1N0M0 (central location) or T2-3N0M0 (any location) NSCLC were treated with proton therapy at 87.5 Gy (relative biological effectiveness, RBE) at 2.5 Gy/fraction in this phase I/II study. All patients underwent treatment simulation with 4-dimensional (4D) computed tomography (CT); internal gross tumor volumes (iGTVs) were delineated on maximal intensity projection (MIP) images and modified by visual verification of the target volume in 10 breathing phases. The iGTV with MIP density was used to design compensators and apertures to account for tumor motion. Therapy consisted of passively scattered protons. All patients underwent repeat 4D CT simulations during treatment to assess the need for adaptive replanning.
Results
At a median follow-up time of 16.3 months (range, 4.8–36.3 months), no patient had experienced grade 4 or 5 toxicity. The most common adverse effect was dermatitis (grade 2, 67%; grade 3, 17%), followed by grade 2 fatigue (44%), grade 2 pneumonitis (11%), grade 2 esophagitis (6%), and grade 2 chest wall pain (6%). Rates of local control were 88.9%, regional lymph node failure 11.1%, and distant metastasis 27.8%. Twelve patients (67%) were still alive at the last follow-up; five had died of metastatic disease and one of preexisting cardiac disease.
Conclusions
Proton therapy to ablative doses is well tolerated and produces promising local control rates for medically inoperable early-stage NSCLC.
doi:10.1016/j.ijrobp.2010.04.049
PMCID: PMC3117089  PMID: 21251767
Proton therapy; non-small cell lung cancer; toxicity; patterns of failure
15.  Oligometastatic Disease at Presentation or Recurrence for Nonsmall Cell Lung Cancer 
Pulmonary Medicine  2012;2012:396592.
Oligometastatic Non-Small Cell Lung Cancer (NSCLC) presents a unique opportunity for potential curative therapy. Improved cancer staging using PET/CT, MRI, and future cellular and molecular staging with circulating tumor cells and/or molecular markers will identify more patients with truly oligometastasis disease that will benefit from definitive local treatment. Recent development of noninvasive local ablative therapy such as stereotactic radiotherapy makes it possible to eradicate multiple local diseases with minimal side effect. Novel systemic therapy may also control systemic spread and therefore make it possible to improve survival by eliminating local diseases. More research, particularly prospective studies, is ideally randomized studies are needed to validate the concept of oligometastasis.
doi:10.1155/2012/396592
PMCID: PMC3413954  PMID: 22900169
16.  STEREOTACTIC BODY RADIATION THERAPY FOR PATIENTS WITH LUNG CANCER PREVIOUSLY TREATED WITH THORACIC RADIATION 
Purpose
Stereotactic body radiation therapy (SBRT) provides excellent local control with acceptable toxicity for patients with early-stage non–small cell lung cancer. However, the efficacy and safety of SBRT for patients previously given thoracic radiation therapy is not known. In this study, we retrospectively reviewed outcomes after SBRT for recurrent disease among patients previously given radiation therapy to the chest.
Materials and Methods
A search of medical records for patients treated with SBRT to the thorax after prior fractionated radiation therapy to the chest at The University of Texas M. D. Anderson Cancer Center revealed 36 such cases. The median follow-up time after SBRT was 15 months. The endpoints analyzed were overall survival, local control, and the incidence and severity of treatment-related toxicity.
Results
SBRT provided in-field local control for 92% of patients; at 2 years, the actuarial overall survival rate was 59%, and the actuarial progression-free survival rate was 26%, with the primary site of failure being intrathoracic relapse. Fifty percent of patients experienced worsening of dyspnea after SBRT, with 19% requiring oxygen supplementation; 30% of patients experienced chest wall pain and 8% Grade 3 esophagitis. No Grade 4 or 5 toxic effects were noted.
Conclusions
SBRT can provide excellent in-field tumor control in patients who have received prior radiation therapy. Toxicity was significant but manageable. The high rate of intrathoracic failure indicates the need for further study to identify patients who would derive the most benefit from SBRT for this purpose.
doi:10.1016/j.ijrobp.2009.09.070
PMCID: PMC3401019  PMID: 20381271
Stereotactic body radiation therapy; retreatment; recurrent lung cancer
17.  EFFECTS OF INTERFRACTIONAL MOTION AND ANATOMIC CHANGES ON PROTON THERAPY DOSE DISTRIBUTION IN LUNG CANCER 
Purpose
Proton doses are sensitive to intra- and interfractional anatomic changes. We analyzed the effects of interfractional anatomic changes in doses to lung tumors treated with proton therapy.
Methods and Materials
Weekly four-dimensional computed tomography (4D-CT) scans were acquired for 8 patients with mobile Stage III non–small cell lung cancer who were actually treated with intensity-modulated photon radiotherapy. A conformal proton therapy passive scattering plan was designed for each patient. Dose distributions were recalculated at end-inspiration and end-expiration breathing phases on each weekly 4D-CT data set using the same plans with alignment based on bone registration.
Results
Clinical target volume (CTV) coverage was compromised (from 99% to 90.9%) in 1 patient because of anatomic changes and motion pattern variation. For the rest of the patients, the mean CTV coverage on the repeated weekly 4D-CT data sets was 98.4%, compared with 99% for the original plans. For all 8 patients, however, a mean 4% increase in the volume of the contralateral lung receiving a dose of at least 5 Gy (V5) and a mean 4.4-Gy increase in the spinal cord maximum dose was observed in the repeated 4D-CT data sets. A strong correlation between the CTV density change resulting from tumor shrinkage or anatomic variations and mean contralateral lung dose was observed.
Conclusions
Adaptive re-planning during proton therapy may be indicated in selected patients with non–small cell lung cancer. For most patients, however, CTV coverage is adequate if tumor motion is taken into consideration in the original simulation and planning processes.
doi:10.1016/j.ijrobp.2008.03.007
PMCID: PMC3401022  PMID: 18486357
Lung cancer; Proton therapy; 4D CT; Intensity-modulated radiation therapy; Adaptive radiotherapy
18.  PROTON STEREOTACTIC BODY RADIATION THERAPY FOR CLINICALLY CHALLENGING CASES OF CENTRALLY AND SUPERIORLY LOCATED STAGE I NON-SMALL CELL LUNG CANCER 
Purpose
To minimize toxicity while maintaining tumor coverage with stereotactic body radiation therapy (SBRT) for centrally or superiorly located stage I non-small-cell lung cancer (NSCLC), we investigated passive-scattering proton therapy (PSPT) and intensity-modulated proton therapy (IMPT).
Materials and Methods
Fifteen patients with centrally or superiorly located (within 2 cm of critical structures) Stage I NSCLC were treated clinically with 3-dimensional photon SBRT (50 Gy in 4 fractions). Photon SBRT plan was compared with the PSPT and IMPT plans. The maximum tolerated dose (MTD) was defined as the dose that exceeded the dose-volume constraints in the critical structures.
Results
Only 6 photon plans satisfied the >95% planning target volume (PTV) coverage and MTD constraints, compared to 12 PSPT plans (p = 0.009) and 14 IMPT plans (p = 0.001). Compared with the photon SBRT plans, the PSPT and IMPT plans significantly reduced the mean total lung dose from 5.4 Gy to 3.5 Gy (p < 0.001) and 2.8 Gy (p < 0.001) and reduced the total lung volume receiving 5 Gy, 10 Gy and 20 Gy (p < 0.001). When the PTV was within 2 cm of the critical structures, the PSPT and IMPT plans significantly reduced the mean maximal dose to the aorta, brachial plexus, heart, pulmonary vessels, and spinal cord.
Conclusions
For centrally or superiorly located stage I NSCLC, proton therapy, particularly IMPT, delivered ablative doses to the target volume and significantly reduced doses to the surrounding normal tissues compared with photon SBRT.
doi:10.1016/j.ijrobp.2010.03.012
PMCID: PMC2952351  PMID: 20615629
stereotactic body radiation therapy; non-small cell lung cancer; centrally located lesion; proton therapy; stage I
19.  Intensity Modulated Radiotherapy for Stage III Non-Small Cell Lung Cancer in the United States: Predictors of Use and Association with Toxicities 
Lung cancer (Amsterdam, Netherlands)  2013;82(2):10.1016/j.lungcan.2013.08.015.
Summary
Background
Intensity modulated radiotherapy for stage III lung cancer has become commonplace in the United States in the absence of randomized controlled trials. We used a large, population-based database to determine which factors led to increased utilization of IMRT and to evaluate associations of IMRT with toxicities.
Methods
The Surveillance, Epidemiology, and End Results (SEER)-Medicare records identified 3,986 individuals aged 66 years or older diagnosed with stage III lung cancer between 2001 and 2007 and treated with IMRT or 3D conformal radiotherapy. Predictors of IMRT use were determined using logistic regression. Associations of IMRT use with diagnosis codes for radiation-related toxicities were evaluated with multivariate proportional hazards regression and propensity-score matching.
Results
Among the 3,986 patients studied, the median age was 75 years, 54.1% were male, and 62% had IIIA disease. Two hundred fifty seven (6.5%) patients received IMRT, with use increasing from from 0.5% in 2001 to 14.7% in 2007 (P<0.001). Key predictors of IMRT delivery included increasing year of diagnosis and treatment in a freestanding center (odds ratio, 2.10; 95% confidence interval [CI], 1.59–2.77, P<0.001); tumor size, stage, and number of radiotherapy fractions delivered were not associated with IMRT use. IMRT use was not associated with a higher burden of lung or esophagus toxicities when compared to 3DCRT.
Conclusion
These findings suggest that practice environment strongly influenced adoption of IMRT for lung cancer. Patient and tumor factors were not significant predictors of IMRT use. Esophagus and lung toxicity rates were similar between IMRT and 3DCRT.
doi:10.1016/j.lungcan.2013.08.015
PMCID: PMC3839043  PMID: 24018022
non-small cell lung cancer; technology utilization; IMRT; radiation technique; comparative effectiveness
20.  Stereotactic ablative radiotherapy for stage I NSCLC: Successes and existing challenges 
Journal of Thoracic Disease  2011;3(3):144-146.
doi:10.3978/j.issn.2072-1439.2011.06.02
PMCID: PMC3256526  PMID: 22263079
21.  Improving Radiation Conformality in the Treatment of Non–Small Cell Lung Cancer 
Seminars in radiation oncology  2010;20(3):171-177.
One of the many challenges of lung cancer radiotherapy is conforming the radiation dose to the target due to tumor/organ motion and the need to spare surrounding critical structures. Evolving radiotherapy technologies, such as four-dimensional (4-D) image-based motion management, daily on-board imaging and adaptive radiotherapy, have enabled us to improve the therapeutic index of radiation therapy for lung cancer by permitting the design of personalized treatments that deliver adequate doses conforming to the target while sparing the surrounding critical normal tissues. Four-dimensional computed tomography (CT) image-based motion management provides an opportunity to individualize target motion margins and reduce the risk of a geographical target miss. Daily on-board imaging and adaptive radiotherapy reduce set-up and motion/anatomy uncertainties over the course of radiotherapy. These achievements in image guidance have permitted the implementation in lung cancer patients of highly conformal treatment delivery techniques that are exquisitely sensitive to organ motion and anatomic change such as intensity-modulated radiation therapy, stereotactic body radiation therapy, and proton therapy. More clinical studies are needed to further optimize conformal radiotherapy using individualized treatment adaptations based on changes in anatomy and tumor motion during the course of radiotherapy and using functional and biological imaging to selectively escalate doses to radioresistant subregions within the tumor.
doi:10.1016/j.semradonc.2010.01.005
PMCID: PMC2905742  PMID: 20652085
22.  Intensity-Modulated Proton Therapy Reduces Normal Tissue Doses Compared with Intensity-Modulated Radiation Therapy or Passive Scattering Proton Therapy and Enables Individualized Radical Radiotherapy for Extensive Stage IIIB Non-Small Cell Lung Cancer: A Virtual Clinical Study 
Purpose
To compare dose-volume histograms (DVHs) for intensity-modulated proton therapy (IMPT) with intensity-modulated radiation therapy (IMRT) and passive scattering proton therapy (PSPT) for stage IIIB non-small cell lung cancer (NSCLC) and explore the possibility of individualized radical radiotherapy.
Methods and Materials
DVHs for IMPT, PSPT, and IMRT designed to deliver IMRT at 60 to 63 Gy, PSPT at 74 Gy, and IMPT at the same doses and individualized radical radiotherapy in patients with extensive stage IIIB NSCLC (N = 10 for each approach) were compared. These patients were selected based on their extensive disease and considered to have no or borderline tolerance of IMRT at 60 to 63 Gy based on normal tissue dose-volume constraints (lung V20<35%, total mean lung dose <20 Gy; spinal cord dose, <45 Gy). The possibility of increasing the total tumor dose with IMPT for each patient without exceeding the dose-volume constraints (maximum tolerant dose, MTD) was also investigated.
Results
Compared with IMRT, IMPT spared more lung, heart, spinal cord, and esophagus even with dose escalation from 63 Gy to 83.5 Gy, with a mean MTD of 74 Gy. Compared with PSPT, IMPT allowed further dose escalation from 74 Gy to mean MTD of 84.4 Gy (range 79.4-88.4 Gy) while keeping all parameters of normal tissue sparing lower or similar. In addition, IMPT prevented lower target coverage in patients with complicated tumor anatomies. Conclusions: IMPT reduces the normal tissue dose and allows individualized radical radiotherapy for extensive stage IIIB NSCLC.
doi:10.1016/j.ijrobp.2009.04.028
PMCID: PMC2868090  PMID: 19660879
Lung cancer; Proton therapy; Intensity-modulated radiation therapy; Passive scattering proton therapy; Intensity-modulated proton therapy
23.  Proton therapy in clinical practice 
Chinese Journal of Cancer  2011;30(5):315-326.
Radiation dose escalation and acceleration improves local control but also increases toxicity. Proton radiation is an emerging therapy for localized cancers that is being sought with increasing frequency by patients. Compared with photon therapy, proton therapy spares more critical structures due to its unique physics. The physical properties of a proton beam make it ideal for clinical applications. By modulating the Bragg peak of protons in energy and time, a conformal radiation dose with or without intensity modulation can be delivered to the target while sparing the surrounding normal tissues. Thus, proton therapy is ideal when organ preservation is a priority. However, protons are more sensitive to organ motion and anatomy changes compared with photons. In this article, we review practical issues of proton therapy, describe its image-guided treatment planning and delivery, discuss clinical outcome for cancer patients, and suggest challenges and the future development of proton therapy.
doi:10.5732/cjc.010.10529
PMCID: PMC4013396  PMID: 21527064
Proton beam; radiotherapy; spread out Bragg peak
24.  Cine CT without a respiratory surrogate in planning of stereotactic radiotherapy for non-small cell lung cancer 
Purpose
To determine whether cine computed tomography (CT) can serve as an alternative to four-dimensional (4D)-CT by providing tumor motion information and producing equivalent target volumes when contoured upon for radiation treatment planning without a respiratory surrogate.
Methods and Materials
Cine CT images from a commercial CT scanner were used to form maximum intensity projection (MIP) and respiratory-averaged CT (RACT) image sets. These image sets then were used together to define targets for radiotherapy. Phantoms oscillating under irregular motion were used to assess differences between contouring on cine CT and 4D-CT. We also retrospectively reviewed image sets for 27 patients at our institution who received stereotactic radiotherapy for stage I non-small cell lung cancer. Patients were included if tumor motion was greater than 1 cm. Lesions were first contoured using MIP and RACT image sets processed from cine CT, then with 4D-CT MIP and 10-phase image sets. Mean ratios of volume magnitude were compared with intraobserver variation, mean centroid shifts were calculated, and volume overlap was assessed with the normalized Dice similarity coefficient index.
Results
The phantom studies demonstrated that cine CT captured a greater extent of irregular tumor motion than 4D-CT, producing a larger tumor volume. The patient studies demonstrated that gross tumor defined on cine imaging was similar to or slightly larger than that defined on 4D-CT.
Conclusions
Cine CT is a promising alternative to 4D-CT for stereotactic radiation treatment planning.
doi:10.1016/j.ijrobp.2008.04.047
PMCID: PMC4160118  PMID: 18644683
4D-CT; cine CT; contouring
25.  Treatment of Radioresistant Stem-Like Esophageal Cancer Cells by an Apoptotic Gene–Armed, Telomerase-Specific Oncolytic Adenovirus 
Purpose
Radioresistance may be caused by cancer stem cells (CSCs). Because CSCs require telomerase to proliferate, a telomerase-specific oncolytic adenoviral vector carrying apoptotic TRAIL and E1A gene (Ad/TRAIL-E1) may preferentially target CSCs.
Experimental Design
We established two pairs of parental and radioresistant (R) esophageal carcinoma cell lines (Seg-1, Seg-1R and TE-2, TE-2R) by fractionated irradiation (FIR). Stem cell markers were measured by Western blotting and flow cytometry. Serial sorting was used to enrich stem-like side population (SP) cells. Telomerase activity, transgene expression, antitumor activity, apoptosis induction, and viral replication were determined in vitro and/or in vivo.
Results
Expression of the stem cell markers β-catenin, Oct3/4, and β1-integrin in Seg-1R cells was 29.4%, 27.5%, and 97.3%, respectively, compared with 4.8%, 14.9%, and 45.3% in Seg-1 cells (P < 0.05). SP levels in Seg-1R and TE-2R cells were 14.6% and 2.7%, respectively, compared with 3.4% and 0.3% in Seg-1 and TE-2 cells. Serial sorting of Seg-1R SP cells demonstrated enrichment of the SP cells. Telomerase activity in Seg-1R, Seg-1R SP and TE-2R cells were significantly higher than Seg-1, Seg-1R non-SP and TE-2 cells respectively (P < 0.05). Seg-1R and TE-2R cells were more sensitive to Ad/TRAIL-E1 than were parental cells. Increased Coxsackie-adenovirus receptor (CAR) and elevated transgene expressions were found in the radioresistant cells. Ad/TRAIL-E1 resulted in significant tumor growth suppression and longer survival in Seg-1R-bearing mice (P < 0.05) with no significant toxicity.
Conclusion
Radioresistant cells established by FIR display CSC-like cell properties. Ad/TRAIL-E1 preferentially targets radioresistant CSC-like cells.
doi:10.1158/1078-0432.CCR-07-1528
PMCID: PMC2387204  PMID: 18451249
Radioresistance; cancer stem-like cells; telomerase-specific oncolytic adenovirus; esophageal; Ad/TRAIL-E1

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