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.
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.
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.
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.
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.
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.
Radioresistant cells established by FIR display CSC-like cell properties. Ad/TRAIL-E1 preferentially targets radioresistant CSC-like cells.
Radioresistance; cancer stem-like cells; telomerase-specific oncolytic adenovirus; esophageal; Ad/TRAIL-E1
To overcome radiation resistance in esophageal adenocarcinoma by tumor-specific apoptotic gene targeting using tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).
Methods and Materials
Adenoviral vector Ad/TRAIL-F/RGD with a tumor specific human telomerase reverse transcription promoter was used to transfer TRAIL gene to human esophageal adenocarcinoma and normal human lung fibroblastic cells (NHLF). Activation of apoptosis was analyzed using western blot, FACS, and TUNEL assay. A human esophageal adenocarcinoma mice model was treated with intratumoral injections of Ad/TRAIL-F/RGD plus local radiotherapy.
The combination of Ad/TRAIL-F/RGD and radiotherapy increased cell-killing effect in all esophageal adenocarcinoma cell lines but not in NHLF cells. This combination also significantly reduced clonogenic formation (p < 0.05) and increased sub-G1 DNA accumulation in cancer cells (p < 0.05). Activation of apoptosis by Ad/TRAIL-F/RGD plus radiotherapy was demonstrated by activation of caspase-9, -8, -3 and cleaved PARP in vitro and TUNEL assay in vivo. Combined Ad/TRAIL-F/RGD and radiotherapy dramatically inhibited tumor growth and prolonged mean survival in esophageal adenocarcinoma model to 31.6 days from 16.7 days for radiotherapy alone and 21.5 days for Ad/TRAIL-F/RGD alone (p< 0.05).
The combination of tumor-specific TRAIL-gene targeting and radiotherapy enhances the effect of suppressing esophageal adenocarcinoma growth and prolonging survival.
Tumor-specific targeting; TRAIL gene therapy; Radiation resistance; Esophageal adenocarcinoma; Apoptosis
To sensitize NSCLC to radiotherapy by tumor-specific delivery of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gene.
The TRAIL gene was delivered to human NSCLC cell lines and normal human bronchial epithelial cells by the replication-defective adenoviral vector Ad/TRAIL-F/RGD using a tumor specific human telomerase reverse transcriptase promoter. Cancer growth was studied using XTT and clonogenic assays. Activation of the apoptosis signal transduction pathway was analyzed in a Western blot, and sub-G1 DNA accumulation was evaluated by a flow cytometry assay. A xenograft mouse model was established, intratumoral injections of Ad/TRAIL-F/RGD were given, and the tumors were locally irradiated at a dose of 5 Gy per tumor; the other groups received one of these treatments alone or a control agent. Apoptosis and TRAIL expression in tumors were analyzed using TUNEL assay and immunohistochemistry respectively.
Ad/TRAIL-F/RGD specifically targets human NSCLC cells without significant effect in NHBE. The combination of TRAIL gene therapy and radiotherapy significantly improved cell-killing effect in all NSCLC cancer cell lines tested (P < 0.05) but not in NHBE. Expression of TRAIL showed a dose-dependent relationship with Ad/TRAIL-F/RGD, and radiation appeared to increase TRAIL expression. Activation of the apoptosis by TRAIL and radiation was demonstrated by activation of caspase-9, caspase-8, caspase-3, and poly-ADP-ribose polymerase and increased DNA sub-G1 accumulation. The combination of TRAIL and radiotherapy significantly inhibited tumor growth and prolonged mean survival in mice bearing human NSCLC to 43.7 days, compared with 23.7 days with TRAIL only, 16.5 days for radiotherapy only (P < 0.05). Combination of Ad/TRAIL-F/RGD and radiation significantly increased apoptosis in animal tumor samples (29.8%, P <0.001) compared with radiation alone (9.7%), Ad/TRAIL-F/RGD alone (13.5%), radiotherapy plus Ad/CMV-GFP (10.3%).
The combination of tumor-specific TRAIL gene therapy and radiotherapy significantly improved therapeutic efficacy in suppressing NSCLC tumor growth and prolonging survival in mice bearing human NSCLC. Ad/TRAIL-F/RGD may improve the therapeutic ratio of radiotherapy in NSCLC.
Tumor-specific targeting; TRAIL gene therapy; radiosensitivity; NSCLC; apoptosis
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.
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.
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.
Stereotactic body radiotherapy; Non-small-cell lung cancer; 18F-fluorodeoxyglucose positron emission tomography; Local recurrence
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.
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.
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.
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.
Proton therapy; concurrent chemotherapy; non-small cell lung cancer; toxicity; patterns of failure; survival
Persistent pathologic mediastinal nodal involvement after induction chemotherapy and surgical resection is a negative prognostic factor for stage III-N2 non-small cell lung cancer patients. This population has high rates of local-regional failure and distant failure, yet the effectiveness of additional therapies is not clear. We assessed the role of consolidative therapies (postoperative radiation therapy and chemotherapy) for such patients.
In all, 179 patients with stage III-N2 non-small cell lung cancer at MD Anderson Cancer Center were treated with induction chemotherapy followed by surgery from 1998 through 2008; 61 patients in this cohort had persistent, pathologically confirmed, mediastinal nodal disease, and were treated with postoperative radiation therapy. Local-regional failure was defined as recurrence at the surgical site or lymph nodes (levels 1 to 14, including supraclavicular), or both. Overall survival was calculated using the Kaplan-Meier method, and survival outcomes were assessed by log rank tests. Univariate and multivariate Cox proportional hazards models were used to identify factors influencing local-regional failure, distant failure, and overall survival.
All patients received postoperative radiation therapy after surgery, but approximately 25% of the patients also received additional chemotherapy: 9 (15%) with concurrent chemotherapy, 4 (7%) received adjuvant sequential chemotherapy, and 2 (3%) received both. Multivariate analysis indicated that additional postoperative chemotherapy significantly reduced distant failure (hazard ratio 0.183, 95% confidence interval: 0.052 to 0.649, p = 0.009) and improved overall survival (hazard ratio 0.233, 95% confidence interval: 0.089 to 0.612, p = 0.003). However, additional postoperative chemotherapy had no affect on local-regional failure.
Aggressive consolidative therapies may improve outcomes for patients with persistent N2 disease after induction chemotherapy and surgery.
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.
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.
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.
Small-cell lung cancer; Involved field radiation; Positron emission tomography; PET; Intensity-modulated radiotherapy; IMRT
Stereotactic ablative radiotherapy (SABR) can achieve excellent local control rates in early-stage non-small cell lung cancer (NSCLC) and has emerged as a standard treatment option for patients who cannot undergo surgery or those with isolated recurrences. However, factors that may predict toxicity or survival are largely unknown. We sought here to identify predictors of survival and pneumonitis after SABR for NSCLC in a relatively large single-institution series.
Subjects were 130 patients with stage I NSCLC treated with four-dimensional computed tomography (4D CT) –planned, on-board volumetric image–guided SABR to 50 Gy in 4 fractions. Disease was staged by positron emission tomography/computed tomography (PET/CT) and scans were obtained again at the second follow-up after SABR.
At a median follow-up time of 26 months, the 2-year local control rate was 98.5%. The median overall survival (OS) time was 60 months, and OS rates were 93.0% at 1 year, 78.2% at 2 years, and 65.3% at 3 years. No patient experienced grade 4–5 toxicity; 15 had radiation pneumonitis (12 [9.3%] grade 2 and 3 [2.3%] grade 3). Performance status, standardized uptake value (SUV)max on staging PET/CT, tumor histology, and disease operability were associated with OS on univariate analysis, but only staging SUVmax was independently predictive on multivariate analysis (P = 0.034). Dosimetric factors were associated with radiation pneumonitis on univariate analysis, but only mean ipsilateral lung dose ≥9.14 Gy was significant on multivariate analysis (P = 0.005).
OS and radiation pneumonitis after SABR for stage I NSCLC can be predicted by staging PET SUVmax and ipsilateral mean lung dose, respectively.
Stereotactic body radiotherapy; Stereotactic ablative radiotherapy; Non-small cell lung cancer; F-fluorodeoxyglucose positron emission tomography; Toxicity; Predictive factors
We studied whether maximum standardized uptake values (SUV) from [18 F] PET/CT predict clinical outcome after concurrent proton/chemotherapy for stage III non-small cell lung cancer (NSCLC).
Eighty-four patients were treated prospectively with 74 Gy(RBE) proton therapy and concurrent chemotherapy. PET/CT scans were available before (SUV1) and within 6 months after (SUV2) treatment. The predictive value of clinical and PET/CT factors were analyzed with univariate and multivariate Cox regression models.
Median survival time was 29.9 months. At 3 years, the local recurrence-free survival (LRFS) rate was 34.8%; distant metastasis-free survival (DMFS), 35.4%; progression-free survival (PFS), 31.2%; and overall survival (OS), 37.2%. Patients with SUV2 ≥3.6 (the median) had high rates of LR (p = 0.021). Of 12 clinicopathologic features evaluated in univariate analysis, only KPS, SUV1, and SUV2 predicted LRFS, DMFS, PFS, and OS (p <0.05). Multivariate analysis showed that KPS (p = 0.025) and SUV2 (p = 0.017) were independently prognostic for LRFS and that SUV1, SUV2, and KPS were independently prognostic for DMFS, PFS, and OS (p <0.05).
SUV2 predicted LRFS, and SUV1 and SUV2 predicted DMFS, PFS, and OS, in patients with stage III NSCLC treated with concurrent chemotherapy and high-dose proton therapy.
Proton therapy; Chemotherapy; Non-small cell lung cancer; PET/CT imaging; Standardized uptake value; Prognostic factors
Oligometastases and oligo-recurrence are among the most important notions of metastatic and recurrent cancer. The concept of oligometastases is related to the notion that cancer patients with 1–5 metastatic or recurrent lesions that could be treated by local therapy achieve long-term survival or cure, while the concept of oligo-recurrence is related to the notion that cancer patients with 1–5 metastatic or recurrent lesions that could be treated by local therapy have controlled primary lesions. Achievement of long-term survival or cure in patients with oligometastases and oligo-recurrence is cancer and organ specific. These facts rely on the seed and soil theory and multiple steps of cancer progression. Oligo-recurrence is considered to have a better prognosis than oligometastases. In patients with oligometastases and oligo-recurrence, the oligometastases and oligo-recurrence are sometimes cured with only local therapy, which is an example of the abscopal effect, previously described in relation to cure of lesions outside of the field of radiation therapy without systemic therapy. Oligometastases and oligo-recurrence can now be cured by less invasive local treatment methods combined with systemic therapy. The mechanisms of oligometastases and oligo-recurrence, as well as novel insights into these important concepts, are presented in this paper.
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.
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.
Proton therapy to ablative doses is well tolerated and produces promising local control rates for medically inoperable early-stage NSCLC.
Proton therapy; non-small cell lung cancer; toxicity; patterns of failure
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.
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.
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.
Stereotactic body radiation therapy; retreatment; recurrent lung cancer
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.
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.
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.
Lung cancer; Proton therapy; 4D CT; Intensity-modulated radiation therapy; Adaptive radiotherapy
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.
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.
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.
stereotactic body radiation therapy; non-small cell lung cancer; centrally located lesion; proton therapy; stage I
Interindividual variation in genetic background may influence the response to chemotherapy and overall survival for patients with advanced-stage non–small cell lung cancer (NSCLC).
To identify genetic variants associated with poor overall survival in these patients, we conducted a genome-wide scan of 307 260 single-nucleotide polymorphisms (SNPs) in 327 advanced-stage NSCLC patients who received platinum-based chemotherapy with or without radiation at the University of Texas MD Anderson Cancer Center (the discovery population). A fast-track replication was performed for 315 patients from the Mayo Clinic followed by a second validation at the University of Pittsburgh in 420 patients enrolled in the Spanish Lung Cancer Group PLATAX clinical trial. A pooled analysis combining the Mayo Clinic and PLATAX populations or all three populations was also used to validate the results. We assessed the association of each SNP with overall survival by multivariable Cox proportional hazard regression analysis. All statistical tests were two-sided.
SNP rs1878022 in the chemokine-like receptor 1 (CMKLR1) was statistically significantly associated with poor overall survival in the MD Anderson discovery population (hazard ratio [HR] of death = 1.59, 95% confidence interval [CI] = 1.32 to 1.92, P = 1.42 × 10−6), in the PLATAX clinical trial (HR of death = 1.23, 95% CI = 1.00 to 1.51, P = .05), in the pooled Mayo Clinic and PLATAX validation (HR of death = 1.22, 95% CI = 1.06 to 1.40, P = .005), and in pooled analysis of all three populations (HR of death = 1.33, 95% CI = 1.19 to 1.48, P = 5.13 × 10−7). Carrying a variant genotype of rs10937823 was associated with decreased overall survival (HR of death = 1.82, 95% CI = 1.42 to 2.33, P = 1.73 × 10−6) in the pooled MD Anderson and Mayo Clinic populations but not in the PLATAX trial patient population (HR of death = 0.96, 95% CI = 0.69 to 1.35).
These results have the potential to contribute to the future development of personalized chemotherapy treatments for individual NSCLC patients.
Many studies have highlighted the role cancer stem cells (CSC) play in the development and progression of various types of cancer including lung and esophageal cancer. More recently, it has been proposed that the presence of CSCs affects treatment efficacy and patient prognosis. In reviewing this new area of cancer biology, we will give an overview of the current literature regarding lung and esophageal CSCs and radioresistance of CSC, and discuss the potential therapeutic applications of these findings.
cancer stem cells; lung cancer; esophageal cancer; radiation therapy
Purpose: Preclinical findings suggest that adding targeted therapies to combination radiation-chemotherapy can enhance treatment efficacy; however, this approach may enhance normal tissue toxicity. We investigated the maximum tolerated dose, dose-limiting toxicities, and response rate when the selective cyclooxygenase-2 inhibitor celecoxib is added to concurrent irinotecan, cisplatin, and radiation therapy for patients with inoperable stage II–III non-small cell lung cancer (NSCLC). Methods and Materials: Eighteen patients were analyzed in a phase I clinical dose-escalation trial. Celecoxib was given daily beginning 5 days before radiation followed by maintenance doses for 12 weeks. Toxicity was graded with the Common Terminology Criteria for Adverse Events V3.0 and response with the World Health Organization system. Primary endpoints were maximum tolerated dose of celecoxib and treatment toxicity; secondary endpoints were response and survival rates. Results: The maximum tolerated dose of celecoxib was not reached, in part owing to discontinuation of the drug supply. At doses of 200 or 400 mg/day, no patients experienced any dose-limiting toxicity (acute grade ≥4 esophagitis or pneumonitis, neutropenic fever or thrombocytopenia requiring transfusion, or acute grade ≥3 diarrhea). Grade 3 toxicities were leukopenia (five patients), fatigue (3), pneumonitis (2), dyspnea (1), pain (1), and esophageal stricture (1). Interestingly, pulmonary fibrosis (a late toxicity) was no more severe in the higher-dose (400-mg) group and may have been less common than in the lower-dose group. The clinical response rate was 100% (8 complete, 10 partial). Two-year rates were: overall survival 65%; local-regional control 69%; distant metastasis-free survival 71%; and disease-free survival 64%. Conclusion: Although preliminary, our results suggest that adding celecoxib to concurrent chemoradiation for inoperable NSCLC is safe and can improve outcome without increasing normal tissue toxicity.
celebrex; CPT-11; cyclooxygenase-2 inhibitor; concurrent chemoradiotherapy; stage II or III non-small cell lung cancer
Treatment of non-small cell lung cancer (NSCLC) with radiotherapy or chemoradiotherapy is often accompanied by the development of esophagitis and pneumonitis. Identifying patients who might be at increased risk for normal tissue toxicity would help in determination of the optimal radiation dose to avoid these events. We profiled 59 single nucleotide polymorphisms (SNPs) from 37 inflammation-related genes in 173 NSCLC patients with stage IIIA/IIIB (dry) disease who were treated with definitive radiation or chemoradiation. For esophagitis risk, nine SNPs were associated with a 1.5- to 4-fold increase in risk, including three PTGS2 (COX2) variants: rs20417 (HR:1.93, 95% CI:1.10–3.39), rs5275 (HR:1.58, 95% CI:1.09–2.27), and rs689470 (HR:3.38, 95% CI:1.09–10.49). Significantly increased risk of pneumonitis was observed for patients with genetic variation in the proinflammatory genes IL1A, IL8, TNF, TNFRSF1B, and MIF. In contrast, NOS3:rs1799983 displayed a protective effect with a 45% reduction in pneumonitis risk (HR:0.55, 95% CI:0.31–0.96). Pneumonitis risk was also modulated by polymorphisms in anti-inflammatory genes, including genetic variation in IL13. rs20541 and rs180925 each resulted in increased risk (HR:2.95, 95% CI:1.14–7.63 and HR:3.23, 95% CI:1.03–10.18, respectively). The cumulative effect of these SNPs on risk was dose-dependent, as evidenced by a significantly increased risk of either toxicity with an increasing number of risk genotypes (P<0.001). These results suggest that genetic variations among inflammation pathway genes may modulate the development of radiation-induced toxicity and, ultimately, help in identifying patients who are at an increased likelihood for such events.
Controversy still exists regarding the long-term outcome of patients whose uninvolved lymph node stations are not prophylactically irradiated for non-small cell lung cancer (NSCLC) treated with definitive radiotherapy. To determine the frequency of elective nodal failure (ENF) and in-field failure (IFF), we examined a large cohort of patients with NSCLC staged with positron emission tomography (PET)/computed tomography (CT) and treated with 3-dimensional conformal radiotherapy (3D-CRT) that excluded uninvolved lymph node stations.
We retrospectively reviewed the records of 115 patients with non-small cell lung cancer treated at our institution with definitive radiation therapy with or without concurrent chemotherapy (CHT). All patients were treated with 3D-CRT, including nodal regions determined by CT or PET to be disease involved. Concurrent platinum-based CHT was administered for locally advanced disease. Patients were analyzed in follow-up for survival, local regional recurrence, and distant metastases (DM).
The median follow-up time was 18 months (3 to 44 months) among all patients and 27 months (6 to 44 months) among survivors. The median overall survival, 2-year actuarial overall survival and disease-free survival were 19 months, 38%, and 28%, respectively. The majority of patients died from DM, the overall rate of which was 36%. Of the 31 patients with local regional failure, 26 (22.6%) had IFF, 5 (4.3%) had ENF and 2 (1.7%) had isolated ENF. For 88 patients with stage IIIA/B, the frequencies of IFF, any ENF, isolated ENF, and DM were 23 (26%), 3 (9%), 1 (1.1%) and 36 (40.9%), respectively. The comparable rates for the 22 patients with early stage node-negative disease (stage IA/IB) were 3 (13.6%), 1(4.5%), 0 (0%), and 5 (22.7%), respectively.
We observed only a 4.3% recurrence of any ENF and a 1.7% recurrence of isolated ENF in patients with NSCLC treated with definitive 3D-CRT without prophylactic irradiation of uninvolved lymph node stations. Thus, distant metastasis and IFF remain the primary causes of treatment failure and cancer death in such patients, suggesting little value of ENI in this cohort.
To determine the optimal approach to delineating patient-specific internal gross target volumes (IGTV) from four-dimensional (4-D) computed tomography (CT) image data sets used in the planning of radiation treatment for lung cancers.
We analyzed 4D-CT image data sets of 27 consecutive patients with non-small-cell lung cancer (stage I: 17, stage III: 10). The IGTV, defined to be the envelope of respiratory motion of the gross tumor volume in each 4D-CT data set was delineated manually using four techniques: (1) combining the gross tumor volume (GTV) contours from ten respiratory phases (IGTVAllPhases); (2) combining the GTV contours from two extreme respiratory phases (0% and 50%) (IGTV2Phases); (3) defining the GTV contour using the maximum intensity projection (MIP) (IGTVMIP); and (4) defining the GTV contour using the MIP with modification based on visual verification of contours in individual respiratory phase (IGTVMIP-Modified). Using the IGTVAllPhases as the optimum IGTV, we compared volumes, matching indices, and extent of target missing using the IGTVs based on the other three approaches.
The IGTVMIP and IGTV2Phases were significantly smaller than the IGTVAllPhases (p < 0.006 for stage I and p < 0.002 for stage III). However, the values of the IGTVMIP-Modified were close to those determined from IGTVAllPhases (p = 0.08). IGTVMIP-Modified also matched the best with IGTVAllPhases.
IGTVMIP and IGTV2Phases underestimate IGTVs. IGTVMIP-Modified is recommended to improve IGTV delineation in lung cancer.