The strategy of definitive chemoradiation with selective surgical salvage in locoregionally advanced esophageal cancer was evaluated in a Phase II trial in Radiation Therapy Oncology Group (RTOG)-affiliated sites.
Methods and Materials
The study was designed to detect an improvement in 1-year survival from 60% to 77.5% (α= 0.05; power = 80%). Definitive chemoradiation involved induction chemotherapy with 5-fluorouracil (5-FU) (650 mg/mg2/day), cisplatin (15 mg/mg2/day), and paclitaxel (200 mg/mg2/day) for two cycles, followed by concurrent chemoradiation with 50.4 Gy (1.8 Gy/fraction) and daily 5-FU (300 mg/mg2/day) with cisplatin (15 mg/mg2/day) over the first 5 days. Salvage surgical resection was considered for patients with residual or recurrent esophageal cancer who did not have systemic disease.
Forty-three patients with nonmetastatic resectable esophageal cancer were entered from Sept 2003 to March 2006. Forty-one patients were eligible for analysis. Clinical stage was ≥T3 in 31 patients (76%) and N1 in 29 patients (71%), with adenocarcinoma histology in 30 patients (73%). Thirty-seven patients (90%) completed induction chemotherapy followed by concurrent chemoradiation. Twenty-eight patients (68%) experienced Grade 3+ nonhematologic toxicity. Four treatment-related deaths were noted. Twenty-one patients underwent surgery following definitive chemoradiation because of residual (17 patients) or recurrent (3 patients) esophageal cancer,and 1 patient because of choice. Median follow-up of live patients was 22 months, with an estimated 1-year survival of 71%.
In this Phase II trial (RTOG 0246) evaluating selective surgical salvage after definitive chemoradiation in locoregionally advanced esophageal cancer, the hypothesized 1-year RTOG survival rate (77.5%) was not achieved (1 year, 71%; 95% confidence interval< 54%–82%).
Esophageal cancer; Chemotherapy; Chemoradiation; Radiation therapy; Salvage surgery
The celiac lymph node axis acts as a gateway for metastatic systemic spread. The need for prophylactic celiac nodal coverage in chemoradiation therapy for esophageal cancer is controversial. Given the improved ability to evaluate lymph node status before treatment via positron emission tomography (PET) and endoscopic ultrasound, we hypothesized that prophylactic celiac node irradiation may not be needed for patients with localized esophageal carcinoma.
Methods and Materials
We reviewed the radiation treatment volumes for 131 patients who underwent definitive chemoradiation for esophageal cancer. Patients with celiac lymph node involvement at baseline were excluded. Median radiation dose was 50.4 Gy. The location of all celiac node failures was compared with the radiation treatment plan to determine whether the failures occurred within or outside the radiation treatment field.
At a median follow-up time of 52.6 months (95% CI 46.1–56.7 months), 6 of 60 patients (10%) without celiac node coverage had celiac nodal failure; in 5 of these patients, these failures represented the first site of recurrence. Of the 71 patients who had celiac coverage, only 5 patients (7%) had celiac region relapse. In multivariate analyses, having a pretreatment-to-posttreatment change in standardized uptake value on PET >52% (odds ratio [OR] 0.198, p=0.0327) and having failure in the clinical target volume (OR 10.72, p=0.001) were associated with risk of celiac region relapse. Of those without celiac coverage, the 6 patients that later developed celiac failure had a worse median overall survival time compared to the other 54 patients who did not fail (median OS time: 16.5 months vs. 31.5 months, p=0.041). Acute and late toxicities were similar in both groups.
While celiac lymph node failures occur in approximately 1 of 10 patients, the lack of effective salvage treatments and subsequent low morbidity may justify prophylactic treatment in distal esophageal cancer patients.
Esophageal cancer; celiac lymph node; failure patterns
Radiosurgery has been successfully used in selected cases to avoid repeat whole-brain irradiation (WBI) in patients with multiple brain metastases of most solid tumor histological findings. Few data are available for the use of radiosurgery for small-cell lung cancer (SCLC).
Methods and Materials
Between November 1999 and June 2009, 51 patients with SCLC and previous WBI and new brain metastases were treated with GammaKnife stereotactic radiosurgery (GKSRS). A median dose of 18 Gy (range, 10–24 Gy) was prescribed to the margin of each metastasis. Patients were followed with serial imaging. Patient electronic records were reviewed to determine disease-related factors and clinical outcomes after GKSRS. Local and distant brain failure rates, overall survival, and likelihood of neurologic death were determined based on imaging results. The Kaplan-Meier method was used to determine survival and local and distant brain control. Cox proportional hazard regression was performed to determine strength of association between disease-related factors and survival.
Median survival time for the entire cohort was 5.9 months. Local control rates at 1 and 2 years were 57% and 34%, respectively. Distant brain failure rates at 1 and 2 years were 58% and 75%, respectively. Fifty-three percent of patients ultimately died of neurologic death. On multivariate analysis, patients with stable (hazard ratio [HR] = 2.89) or progressive (HR = 6.98) extracranial disease (ECD) had worse overall survival than patients without evidence of ECD (p = 0.00002). Concurrent chemotherapy improved local control (HR = 89; p = 0.006).
GKSRS represents a feasible salvage option in patients with SCLC and brain metastases for whom previous WBI has failed. The status of patients’ ECD is a dominant factor predictive of overall survival. Local control may be inferior to that seen with other cancer histological results, although the use of concurrent chemotherapy may help to improve this.
Small cell lung cancer; Brain metastases; Stereotactic radiosurgery
The recently activated RTOG studies on stereotactic body radiation therapy (SBRT) of non-small cell lung cancer (NSCLC) require tissue density heterogeneity correction, where the high and intermediate dose compliance criteria were established based on superposition-algorithm dose calculations. The study was aimed to compare superposition-algorithm dose calculations with Monte Carlo (MC) dose calculations for SBRT NSCLC treatment and to evaluate whether compliance criteria need to be adjusted for MC dose calculations.
Materials and Methods
Fifteen RTOG 0236 study sets were used. The PTV volumes range from 10.7 to 117.1 cm3. SBRT conformal treatment plans were generated using CMS XiO treatment planning software with superposition algorithm to meet the dosimetric high and intermediate compliance criteria recommended by the RTOG 0813 protocol. The plans were recalculated using the MC algorithm of a CMS Monaco treatment planning system. Tissue density heterogeneity correction was applied in both calculations.
Overall, the dosimetric quantities of the MC calculations have larger magnitudes than those of the superposition calculations. On average, R100% (ratio of prescription isodose volume to PTV), R50% (ratio of 50% prescription isodose volume to PTV), D2cm (maximal dose 2 cm from PTV in any direction in percentage of prescription dose), and V20 (percentage of lung receiving dose equal to or larger than 20 Gy) increased by 9%, 12%, 7%, and 18%, respectively. In the superposition plans, 3 cases did not meet the criteria for R50% or D2cm. In the MC recalculated plans, 8 cases did not meet the criteria for R100%, R50%, or D2cm. After re-optimization with MC calculations, 5 cases did not meet the criteria for R50% or D2cm.
The results indicate that the dosimetric criteria, e.g., the criteria for R50%, recommended by RTOG 0813 protocol, may need to be adjusted when MC dose calculation algorithm is employed.
RTOG; stereotactic body radiation therapy; non-small-cell lung cancer; heterogeneity correction; Monte Carlo
Accelerated tumor repopulation has significant implications in low-dose-rate (LDR) brachytherapy. Repopulation onset time remains undetermined for cervical cancer. The purpose of this study was to determine the onset time of accelerated repopulation in cervical cancer using clinical data.
Methods and Materials
The linear-quadratic (LQ) model extended for tumor repopulation was used to analyze the clinical data and MRI-based 3D tumor volumetric regression data of 80 cervical cancer patients who received external beam radiotherapy (EBRT) and low dose rate (LDR) brachytherapy. The LDR dose was converted to EBRT dose in 1.8 Gy fractions using the LQ formula, and the total dose ranged from 61.4 to 99.7 Gy. The patients were divided into 11 groups according to total dose and treatment time. The tumor control probability (TCP) was calculated for each group. The least χ2 method was used to fit the TCP data with two free parameters: onset time (Tk) of accelerated repopulation and the number of clonogens (K) while other LQ model parameters were adopted from the literature, due to the limited patient data.
Among the 11 patient groups, TCP varied from 33% to 100% as a function of radiation dose and overall treatment time. Higher dose and shorter treatment duration were associated higher TCP. Using the LQ model, the best fit was achieved with the onset time Tk=19 days, K=139, with uncertainty ranges of (11, 22) days for Tk, and (48, 1822) for K, respectively.
This is the first report of accelerated repopulation onset time in cervical cancer, derived directly from the clinical data using the LQ model. Our study verifies that accelerated repopulation does exist in cervical cancer and has a relatively short onset time. Dose escalation may be required to compensate for the effects of tumor repopulation if the radiation therapy course is protracted.
Cervical cancer; Radiation therapy; Tumor control probability; Tumor repopulation onset time; Linear-quadratic model
To demonstrate the feasibility of a dedicated breast computed tomography (bCT) platform to deliver rotational kilovoltage external beam radiation therapy (kVEBRT) for partial breast irradiation (PBI), whole breast irradiation (WBI) and dose painting.
Methods and Materials
Rotational kV-EBRT using the geometry of a prototype bCT platform was evaluated via Monte Carlo simulator. A point source emitting 178 keV photons (approximating a 320 kVp spectrum with 4 mm copper filtration) was rotated around a 14 cm voxelized polyethylene disk (0.1 cm tall) or cylinder (9 cm tall) to simulate primary and primary plus scattered photon interactions, respectively. Simulations were also performed using voxelized bCT patient images. Beam collimation was varied in the x-y plane (1–14 cm) and in the z-direction (0.1–10 cm). Dose painting for multiple foci, line and ring distributions was demonstrated using multiple rotations with varying beam collimation. Simulations using the scanner’s native hardware (120 kVp filtered by 0.2 mm copper) were validated experimentally.
As the x-y collimator was narrowed, the 2D dose profiles shifted from a cupped profile with high edge dose to an increasingly peaked central dose distribution with sharp dose fall-off. Using a 1 cm beam, the cylinder edge dose was less than 7% of dose deposition at the cylinder center. Simulations using 120 kVp x-rays showed distributions similar to experimental measurements. A homogeneous dose distribution (< 2.5% dose fluctuation) with a 20% decrease in dose deposition at the cylinder edge (i.e. skin sparing) was demonstrated by weighted summation of four dose profiles using different collimation widths. Simulations using patient bCT images demonstrated the potential for treatment planning and image-guided radiation therapy (IGRT).
Rotational kV-EBRT for PBI, dose painting, and WBI with skin sparing is feasible on a bCT platform with the potential for high-resolution IGRT.
breast cancer; rotational kilovoltage radiation therapy; computed tomography; Monte Carlo simulation
We investigated potential associations between single-nucleotide polymorphisms (SNPs) in the heat shock protein beta-1 (HSPB1) gene and overall survival in U.S. patients with non–small-cell lung cancer (NSCLC).
Materials and Methods
Using available genomic DNA samples from 224 patients with NSCLC treated with definitive radio(chemo)therapy, we genotyped two SNPs of HSPB1 (rs2868370 and rs2868371). We used both Kaplan-Meier cumulative probability and Cox proportional hazards analyses to evaluate the effect of HSPB1 genotypes on survival.
Our cohort comprised 117 men and 107 women, mostly white (79.5%), with a median age of 70 years. The median radiation dose was 66 Gy (range 63–87.5 Gy), and 183 patients (82%) received concurrent platinum-based chemotherapy. The most common genotype of the rs2868371 SNP was CC (61%). Univariate and multivariate analyses showed that this genotype was associated with poorer survival than carriers of CG/GG genotypes (univariate hazard ratio [HR]=1.39, 95% confidence interval [CI] 1.02–1.90, P = 0.037; multivariate HR=1.39; 95% CI 1.01–1.92; P = 0.045).
Our results show that the CC genotype of HSPB1 rs2868371 was associated with poorer overall survival in patients with NSCLC after radio(chemo)therapy, findings that contradict those of a previous study of Chinese patients. Validation of our findings with larger numbers of similar patients is needed, as are mechanical and clinical studies to determine the mechanism underlying these associations.
Non–small cell lung cancer; radiation therapy; overall survival; single-nucleotide polymorphisms; heat shock protein beta-1
Although variability in target delineation has been studied in head and neck cancer, variability in normal tissue delineation has not. This study evaluated the variability of organ at risk (OAR) delineation and the resulting impact on intensity-modulated radiation therapy (IMRT) treatment plan optimization.
Methods and Materials
An expert panel of three radiation oncologists jointly delineated OARs, including the parotid and submandibular glands (SM), pharyngeal constrictors (PC), larynx, and glottis (GL), in 10 patients with advanced oropharynx cancer in 3 contouring sessions, spaced at least 1 week apart. Contour variability and uncertainty, as well as their dosimetric impact on IMRT planning for each case, were assessed.
The mean difference in total volume for each OAR was 1cm3 (σ 0.5). Mean fractional overlap was 0.7 (σ 0.1), and was highest (0.8) for the larynx and bilateral SMs and parotids, and lowest (0.5) for the PC. There were considerable spatial differences in contours, with the ipsilateral parotid and PC displaying the most variability (0.9 cm), which was most prominent in cases where tumors obliterated fat planes. Both SMs and the glottis had the smallest differences (0.5 cm). The mean difference in OAR dose was 0.9 Gy (range 0.6-1.1, σ0.1), with the smallest difference for the GL and largest for both SMs and the larynx.
Despite substantial difference in OAR contours, optimization was barely affected, with a 0.9 Gy mean difference between optimizations, suggesting relative insensitivity of dose distributions for IMRT of oropharynx cancer to the extent of OARs.
organs at risk; contour variability; adaptive planning; head and neck cancer
Exposure to ionizing radiation is an established risk factor for breast cancer. Radiation exposure during infancy, childhood, and adolescence confers the highest risk. Although radiation is a proven mammary carcinogen, it remains unclear where it acts in the complex multistage process of breast cancer development. In this study, we investigated the long-term pathophysiologic effects of ionizing radiation at a dose (2 Gy) relevant to fractionated radiotherapy.
Methods and Materials
Adolescent (6–8 weeks old; n = 10) female C57BL/6J mice were exposed to 2 Gy total body γ-radiation, the mammary glands were surgically removed, and serum and urine samples were collected 2 and 12 months after exposure. Molecular pathways involving estrogen receptor-α (ERα) and phosphatidylinositol-3-OH kinase (PI3K)-Akt signaling were investigated by immunohistochemistry and Western blot.
Serum estrogen and urinary levels of the oncogenic estrogen metabolite (16αOHE1) were significantly increased in irradiated animals. Immunostaining for the cellular proliferative marker Ki-67 and cyclin-D1 showed increased nuclear accumulation in sections of mammary glands from irradiated vs. control mice. Marked increase in p85α, a regulatory sub-unit of the PI3K was associated with increase in Akt, phospho-Akt, phospho-BAD, phospho-mTOR, and c-Myc in irradiated samples. Persistent increase in nuclear ERα in mammary tissues 2 and 12 months after radiation exposure was also observed.
Taken together, our data not only support epidemiologic observations associating radiation and breast cancer but also, specify molecular events that could be involved in radiation-induced breast cancer.
Radiation; Estradiol; Estrogen; Estrogen receptor α; Estrogen metabolite
To test whether reducing radiation dose to uninvolved bladder while maintaining dose to the tumor would reduce side effects without impairing local control in the treatment of muscle-invasive bladder cancer.
Methods and Materials
In this phase III multicenter trial, 219 patients were randomized to standard whole-bladder radiation therapy (sRT) or reduced high-dose volume radiation therapy (RHDVRT) that aimed to deliver full radiation dose to the tumor and 80% of maximum dose to the uninvolved bladder. Participants were also randomly assigned to receive radiation therapy alone or radiation therapy plus chemotherapy in a partial 2 × 2 factorial design. The primary endpoints for the radiation therapy volume comparison were late toxicity and time to locoregional recurrence (with a noninferiority margin of 10% at 2 years).
Overall incidence of late toxicity was less than predicted, with a cumulative 2-year Radiation Therapy Oncology Group grade 3/4 toxicity rate of 13% (95% confidence interval 8%, 20%) and no statistically significant differences between groups. The difference in 2-year locoregional recurrence free rate (RHDVRT − sRT) was 6.4% (95% confidence interval −7.3%, 16.8%) under an intention to treat analysis and 2.6% (−12.8%, 14.6%) in the “per-protocol” population.
In this study RHDVRT did not result in a statistically significant reduction in late side effects compared with sRT, and noninferiority of locoregional control could not be concluded formally. However, overall low rates of clinically significant toxicity combined with low rates of invasive bladder cancer relapse confirm that (chemo)radiation therapy is a valid option for the treatment of muscle-invasive bladder cancer.
To evaluate the long-term toxicity, cosmesis, and local control of accelerated partial breast irradiation with implant brachytherapy after wide local excision for Stage T1N0 breast cancer (BCa).
Materials and Methods
Between 1997 and 2001, 50 patients with Stage T1N0M0 BCa were treated in a Phase I–II protocol using low-dose-rate accelerated partial breast irradiation with implant brachytherapy after wide local excision and lymph node surgery. The total dose was escalated in three groups: 50 Gy (n = 20), 55 Gy (n = 17), and 60 Gy (n = 13). Patient- and physician-assessed breast cosmesis, patient satisfaction, toxicity, mammographic abnormalities, repeat biopsies, and disease status were prospectively evaluated at each visit. Kendall’s tau (τβ) and logistic regression analyses were used to correlate outcomes with dose, implant volume, patient age, and systemic therapy.
The median follow-up period was 11.2 years (range, 4–14). The patient satisfaction rate was 67%, 67% reported good-excellent cosmesis, and 54% had moderate-severe fibrosis. Higher dose was correlated with worse cosmetic outcome (τβ 0.6, p < .0001), lower patient satisfaction (τβ 0.5, p < .001), and worse fibrosis (τβ 0.4, p = .0024). Of the 50 patients, 35% had fat necrosis and 34% developed telangiectasias ≥1 cm2. Grade 3–4 late skin and subcutaneous toxicities were seen in 4 patients (9%) and 6 patients (13%), respectively, and both correlated with higher dose (τβ 0.3–0.5, p ≤ .01). One patient had Grade 4 skin ulceration and fat necrosis requiring surgery. Mammographic abnormalities were seen in 32% of the patients, and 30% underwent repeat biopsy, of which 73% were benign. Six patients had ipsilateral breast recurrence: five elsewhere in the breast, and one at the implant site. One patient died of metastatic BCa after recurrence. The 12-year actuarial local control, recurrence-free survival, and overall survival rate was 85% (95% confidence interval, 70–97%), 72% (95% confidence interval, 54–86%), and 87% (95% confidence interval, 73–99%), respectively.
Low-dose-rate accelerated partial breast irradiation with implant brachytherapy provides acceptable local control in select early-stage BCa patients. However, treatment-related toxicity and cosmetic complications were significant with longer follow-up and at higher doses.
Accelerated partial breast irradiation; Implant brachytherapy; Early-stage breast cancer; Low-dose-rate; Long-term cosmesis
As the recommended radiation dose for non-small cell lung cancer (NSCLC) increases, meeting dose constraints for critical structures like the brachial plexus becomes increasingly challenging, particularly for tumors in the superior sulcus. In this retrospective analysis, we compared dose-volume histogram information with the incidence of plexopathy to establish the maximum tolerated dose to the brachial plexus.
Methods and Materials
We identified 90 patients with NSCLC treated with definitive chemoradiation from March 2007 through September 2010 who had received>55 Gy to the brachial plexus. We used a multi-atlas segmentation method combined with deformable image registration to delineate the brachial plexuson the original planning CT scans and scoredplexopathy according to the Common Terminology Criteria for Adverse Events v4.03.
The median radiation dose to the brachial plexus was 70 Gy (range 56-87.5 Gy, 1.5-2.5 Gy/fraction). At a median follow-up time of 14.0 months, 14 patients had had brachial plexopathy (16%) (8 [9%] grade 1 and 6 [7%] grade ≥2); median time to symptom onset was 6.5 months (range 1.4-37.4 months). On multivariate analysis, receipt of median brachial plexus dose >69 Gy(odds ratio [OR] 10.091, 95% confidence interval [CI] 1.512-67.331, P=0.005), maximum dose >75 Gy to 2 cm3 of the brachial plexus(OR 4.909, 95% CI 0.966-24.952, P=0.038), and the presence of plexopathy before irradiation(OR 4.722, 95% CI 1.267-17.606, P=0.021) were independent predictors of brachial plexopathy.
For lung cancers near the apical region, brachial plexopathy is a major concern for high-dose radiation therapy. We developed a computer-assisted image segmentation method which allowed us to rapidly and consistently contour the brachial plexus and establish the dose limits to minimize the risk of brachial plexopathy. Our results could be used as a guideline in future prospective trialswithhigh dose radiation therapy for unresectable lung cancer.
brachial plexopathy; superior sulcus tumor; dose escalation; normal tissue toxicity; deformable image registration
To evaluate how changes in tumor hypoxia, according to serial fluorine-18-labeled fluoro-misonidazole (18F-FMISO) positron emission tomography (PET) imaging, affect the efficacy of intensity-modulated radiotherapy (IMRT) dose painting.
Methods and Materials
Seven patients with head and neck cancers were imaged twice with FMISO PET, separated by 3 days, before radiotherapy. Intensity-modulated radiotherapy plans were designed, on the basis of the first FMISO scan, to deliver a boost dose of 14 Gy to the hypoxic volume, in addition to the 70-Gy prescription dose. The same plans were then applied to hypoxic volumes from the second FMISO scan, and the efficacy of dose painting evaluated by assessing coverage of the hypoxic volumes using Dmax, Dmin, Dmean, D95, and equivalent uniform dose (EUD).
Similar hypoxic volumes were observed in the serial scans for 3 patients but dissimilar ones for the other 4. There was reduced coverage of hypoxic volumes of the second FMISO scan relative to that of the first scan (e.g., the average EUD decreased from 87 Gy to 80 Gy). The decrease was dependent on the similarity of the hypoxic volumes of the two scans (e.g., the average EUD decrease was approximately 4 Gy for patients with similar hypoxic volumes and approximately 12 Gy for patients with dissimilar ones).
The changes in spatial distribution of tumor hypoxia, as detected in serial FMISO PET imaging, compromised the coverage of hypoxic tumor volumes achievable by dose-painting IMRT. However, dose painting always increased the EUD of the hypoxic volumes.
Tumor hypoxia; Dose painting; 18F-FMISO PET
To construct a maximally predictive model of the risk of severe acute esophagitis (AE) for patients who receive definitive radiation therapy (RT) for non–small-cell lung cancer.
Methods and Materials
The dataset includes Washington University and RTOG 93-11 clinical trial data (events/patients: 120/374, WUSTL = 101/237, RTOG9311 = 19/137). Statistical model building was performed based on dosimetric and clinical parameters (patient age, sex, weight loss, pretreatment chemotherapy, concurrent chemo-therapy, fraction size). Awide range of dose–volume parameters were extracted from dearchived treatment plans, including Dx, Vx, MOHx (mean of hottest x% volume), MOCx (mean of coldest x% volume), and gEUD (generalized equivalent uniform dose) values.
The most significant single parameters for predicting acute esophagitis (RTOG Grade 2 or greater) were MOH85, mean esophagus dose (MED), and V30. A superior–inferior weighted dose-center position was derived but not found to be significant. Fraction size was found to be significant on univariate logistic analysis (Spearman R = 0.421, p < 0.00001) but not multivariate logistic modeling. Cross-validation model building was used to determine that an optimal model size needed only two parameters (MOH85 and concurrent chemotherapy, robustly selected on bootstrap model-rebuilding). Mean esophagus dose (MED) is preferred instead of MOH85, as it gives nearly the same statistical performance and is easier to compute. AE risk is given as a logistic function of (0.0688 * MED+1.50 * ConChemo-3.13), where MED is in Gy and ConChemo is either 1 (yes) if concurrent chemotherapy was given, or 0 (no). This model correlates to the observed risk of AE with a Spearman coefficient of 0.629 (p < 0.000001).
Multivariate statistical model building with cross-validation suggests that a two-variable logistic model based on mean dose and the use of concurrent chemotherapy robustly predicts acute esophagitis risk in combined-data WUSTL and RTOG 93-11 trial datasets.
Acute esophagitis; Lung cancer; NTCP; Radiotherapy
To quantify the risk of second primary breast cancer in the contralateral breast (CB) following radiation therapy (RT) for first breast cancer.
Methods and Materials
The study population included participants in the Women’s Environmental, Cancer, and Radiation Epidemiology (WECARE) study: 708 cases (women with asynchronous bilateral breast cancer) and 1399 controls (women with unilateral breast cancer) counter-matched on radiation treatment. Participants were < 55 years of age at first breast cancer. Absorbed doses to quadrants of the CB were estimated. Rate ratios (RR) and 95% confidence intervals were calculated using multivariable-adjusted conditional logistic regression models.
Across all patients, the mean radiation dose to the specific quadrant of the CB tumor was 1.1 Gy. Women < 40 years of age who received > 1.0 Gy of absorbed dose to the specific quadrant of the CB had a 2.5-fold greater risk for CB cancer than unexposed women (RR=2.5, 95% CI= 1.4 – 4.5). No excess risk was observed in women >40 years of age. Women < 40 years of age with followup periods > 5 years had a RR of 3.0 (95% CI=1.1–8.1), and the dose response was significant (excess RR per Gy of 1.0, 95% CI=0.1–3.0).
Women < 40 years of age who received a radiation dose > 1.0 Gy to the CB had an elevated, long-term risk of developing a second primary CB cancer. The risk is inversely related to age at exposure and is dose dependent.
Contralateral breast; Radiation risk; Secondary breast cancer
Previous recursive partitioning analysis (RPA) of patients with malignant glioma (glioblastoma multiforme [GBM] and anaplastic astrocytoma [AA]) produced six prognostic groups (I-VI) classified by six factors1. We sought here to determine whether the classification for GBM could be improved by using an updated RTOG GBM database excluding AA and by considering additional baseline variables.
Patients and Methods
The new analysis considered 42 baseline variables and 1672 GBM patients from the expanded RTOG glioma database. Patients receiving radiation only were excluded such that all patients received radiation+carmustine. “Radiation dose received” was replaced with “radiation dose assigned.” The new RPA models were compared to the original model by applying to a test dataset comprising 488 patients from six other RTOG trials. Fitness of the original and new models was evaluated using explained variation.
The original RPA model explained more variations in survival in the test dataset than did the new models (20% vs. 15%) and was therefore chosen for further analysis. It was reduced by combining classes V and VI to produce three prognostic classes (III, IV, V+VI), as classes V and VI had indistinguishable survival in the test dataset. The simplified model did not further improve performance (explained variation 18% vs. 20%) but is easier to apply because it involves only four variables:age, performance status, extent of resection, and neurologic function. Applying this simplified model to the updated GBM database resulted in three distinct classes with median survival times of 17.1, 11.2, and 7.5 months for classes III, IV, and V+VI, respectively.
The final model, the simplified original RPA model combining classes V and VI, resulted in three distinct prognostic groups defined by age, performance status, extent of resection, and neurologic function. This classification will be used in future RTOG GBM trials.
Glioblastoma; prognostic factors; recursive partitioning analysis; RTOG
To investigate whether selected high-risk MMP7 single nucleotide polymorphisms influence tumor biology or clinical outcomes in patients with clinical early-stage prostate cancer undergoing prostatectomy.
Two hundred twelve human prostate cancer patients treated with radical prostatectomy were included in the study. Median follow-up was approximately 9.8 years. Genotyping was performed using TaqMan™ technology and custom-designed probes. Three single nucleotide polymorphisms within various regions of the MMP7 gene were assessed with correlation to age at diagnosis, margin status, extracapsular extension, lymph node metastasis, local recurrence and tumor survival in paraffin-embedded prostate tissue specimens from patients with early-stage prostate cancer receiving radical prostatectomy alone.
Rs10895304 was the sole significant polymorphism. The SNP correlated to increased recurrence rates in post-prostatectomy patients (P<0.0094, Log Rank Test). The frequency of the homozygous dominant (A/A) is 74%, the heterozygote (A/G) is 20% and the homozygous recessive (G/G) is 6%. Multivariate analysis (using Chi square analysis) did not detect a confounding relationship between recurrence and age at diagnosis, PSA or Gleason score. None of the other assayed polymorphisms were significant, and no correlations were made to other clinical variables.
The G allele of the rs10895304 polymorphism is predictive of increased local recurrence risk in patients with clinically localized prostate cancer. For this subset of patients, prostatectomy alone may not be adequate for local control. This is a novel and relevant marker that should be evaluated for improved risk stratification of patients who may be candidates for early post-operative radiation therapy to improve local control.
polymorphism; MMP7; matrilysin; prostate cancer; prognosis; recurrence
Conformal radiation therapy in the post-prostatectomy setting requires accurate setup and localization of the prostatic fossa. In this series, we report prostate bed localization and motion characteristics using data collected from implanted radiofrequency transponders.
Materials and Methods
The Calypso 4D Localization System uses three implanted radiofrequency transponders for daily target localization and real-time tracking throughout a course of radiation therapy. We reviewed the localization and tracking reports of 20 patients who received ultrasound-guided placement of Calypso transponders within the prostate bed prior to a course of intensity modulated radiation therapy at Fox Chase Cancer Center.
At localization, prostate bed displacement relative to bony anatomy exceeded 5 mm in 9% of fractions in the Anterior-Posterior (A-P) direction, and 21% of fractions in the Superior-Inferior (S-I) direction. The three-dimensional vector length from skin marks to Calypso alignment exceeded 1 cm in 24% of all 652 fractions with available setup data. During treatment, the target exceeded the 5 mm tracking limit for at least 30 seconds in 11% of all fractions, generally in the A-P or S-I directions. In the A-P direction, target motion was twice as likely to move posteriorly, towards the rectum, than anteriorly. 15% of all treatments were interrupted for repositioning, and 70% of patients were repositioned at least once during their treatment course.
Set-up errors and motion of the prostatic fossa during radiotherapy are nontrivial, leading to potential undertreatment of target and excess normal tissue toxicity if not taken into account during treatment planning. Localization and real-time tracking of the prostate bed via implanted Calypso transponders can be used to improve the accuracy of plan delivery.
post-prostatectomy; tracking; localization; motion
Childhood cancer survivors have an increased risk of secondary sarcomas. To better identify those at risk, the relationship between therapeutic dose of chemotherapy and radiation and secondary sarcoma should be quantified.
Methods and Materials
We conducted a nested case-control study of secondary sarcomas (105 cases, 422 matched controls) in a cohort of 14,372 childhood cancer survivors. Radiation dose at the second malignant neoplasm (SMN) site and use of chemotherapy were estimated from detailed review of medical records. Odds ratios (ORs) and 95% confidence intervals were estimated by conditional logistic regression. Excess odds ratio (EOR) was modeled as a function of radiation dose, chemotherapy, and host factors.
Sarcomas occurred a median of 11.8 years (range: 5.3-31.3 years) from original diagnosis. Any exposure to radiation was associated with increased risk of subsequent sarcoma (OR = 4.1, 95% CI = 1.8-9.5). A dose-response relation was observed, with elevated risks at doses between 10 - 29.9 Gy (OR = 15.6, 95% CI = 4.5-53.9), 30 - 49.9 Gy (OR = 16.0, 95% CI 3.8-67.8) and >50 Gy (OR = 114.1, 95% CI 13.5-964.8). Anthracycline exposure was associated with sarcoma risk (OR = 3.5, 95% CI = 1.6-7.7) adjusting for radiation dose, other chemotherapy, and primary cancer. Adjusting for treatment, survivors with a first diagnosis of Hodgkin lymphoma (HL; OR=10.7, 95% CI = 3.1-37.4) or primary sarcoma (OR=8.4, 95% CI = 3.2-22.3) were more likely to develop a sarcoma.
Of the risk factors evaluated, radiation exposure was the most important for secondary sarcoma development in childhood cancer survivors; anthracycline chemotherapy exposure was also associated with increased risk.
Childhood cancer survivors; secondary sarcomas; radiation late effects
Radiation-induced gastric bleeding has been poorly understood. In this study, we describe dosimetric predictors for gastric bleeding after fractionated radiotherapy and compare several predictive models.
Materials & Methods
The records of 139 sequential patients treated with 3-dimensional conformal radiotherapy (3D-CRT) for intrahepatic malignancies between January 1999 and April 2002 were reviewed. Median follow-up was 7.4 months. Logistic regression and Lyman normal tissue complication probability (NTCP) models for the occurrence of ≥ grade 3 gastric bleed were fit to the data. The principle of maximum likelihood was used to estimate parameters for all models.
Sixteen of 116 evaluable patients (14%) developed gastric bleeds, at a median time of 4.0 months (mean 6.5 months, range 2.1–28.3 months) following completion of RT. The median and mean of the maximum doses to the stomach were 61 and 63 Gy (range 46 Gy–86 Gy), respectively, after bio-correction to equivalent 2 Gy daily fractions. The Lyman NTCP model with parameters adjusted for cirrhosis was most predictive of gastric bleed (AUROC=0.92). Best fit Lyman NTCP model parameters were n =0.10, and m =0.21, with TD50(normal) =56 Gy and TD50(cirrhosis) = 22 Gy. The low n value is consistent with the importance of maximum dose; a lower TD50 value for the cirrhosis patients points out their greater sensitivity.
This study demonstrates that the Lyman NTCP model has utility for predicting gastric bleeding, and that the presence of cirrhosis greatly increases this risk. These findings should facilitate the design of future clinical trials involving high-dose upper abdominal radiation.
NTCP; Gastric Bleed; Hepatic Irradiation; Complications
To present the largest retrospective series investigating the effect of aspirin and statins, which are hypothesized to have anti-neoplastic properties, on biochemical failure (BF, Nadir+2) following prostate radiotherapy (RT).
METHODS AND MATERIALS
Between 1989 and 2006, 2051 men with clinical clinically localized prostate cancer received definitive RT alone (median dose: 76 Gy). Aspirin or statin use (defined as any use at the time of RT or during follow-up) was 36% and 34%, respectively. The primary endpoint of the study an interval to BF (IBF) < 18, which has been shown to be the single strongest predictor of distant metastasis, prostate cancer survival, and overall survival following RT. Patient demographic characteristics and tumor staging factors were assessed in regard of associations with the endpoint. Univariate analysis was performed using the Chi-square test for categorical variables and the Wilcoxon test for continuous variables. Multivariable analysis was done via a multiple logistic regression.
The median follow-up was 75 months. Univariately, IBF < 18 months was associated with aspirin non-use (p<0.0001), statin non-use (p<0.0001), anticoagulant non-use (p=0.0006), cardiovascular disease (p =0.0008), and PSA (continuous, p=0.008); but, not Gleason score, age, RT dose, or T-stage. On multivariate analysis, only aspirin non-use (p=0.0012, OR=2.052, CI:1.328–3.172) and statin non-use (p=0.0002, OR=2.465, CI: 1.529–3.974) were associated with IBF < 18 months.
In patients who received RT for prostate cancer, aspirin or statin non-use was associated with early BF, a harbinger of distant metastasis and death. Further study is needed to confirm these findings and to determine the optimal dosing, schedule, as well as the relative benefits and risks of both therapies in combination with RT.
Radiotherapy; prostate cancer; aspirin; statin
To compare the quality of volumetric modulated arc therapy (VMAT) or intensity-modulated radiation therapy (IMRT) plans generated by an automated inverse planning system with that of dosimetrist-generated IMRT treatment plans for patients with stage III lung cancer.
Methods and Materials
Two groups of eight patients with stage III lung cancer were randomly selected. For group I, the dosimetrists spent their best effort in designing IMRT plans to compete with the automated inverse planning system (mdaccAutoPlan); for group II, the dosimetrists were not in competition and spent their regular effort. Five experienced radiation oncologists independently blind-reviewed and ranked the three plans for each patient, a rank of “1” being the best and “3” the worst. Dosimetric measures were also performed to quantitatively evaluate the three types of plans.
Blind rankings from different oncologists were generally consistent. For group I, the auto-VMAT, auto-IMRT, and manual-IMRT plans received average ranks of 1.6, 2.13, and 2.18, respectively. The auto-VMAT plans in group I had 10% higher PTV conformality and 24% lower esophagus V70 than the manual-IMRT plans; they also resulted in over 20% higher complication-free tumor control probability (p+) than either type of IMRT plans. The auto- and manual-IMRT plans in this group yielded generally comparable dosimetric measures. For group II, the auto-VMAT, auto-IMRT, and manual-IMRT plans received average ranks of 1.55, 1.75, and 2.75, respectively. Compared to the manual-IMRT plans in this group, the auto-VMAT plans and the auto-IMRT plans showed, respectively, 17% and 14% higher PTV dose conformality, 8% and 17% lower mean lung dose, 17% and 26% lower mean heart dose, and 36% and 23% higher p+.
mdaccAutoPlan is capable of generating high-quality VMAT and IMRT treatment plans for stage III lung cancer. Manual-IMRT plans could achieve quality similar to auto-IMRT plans if best effort were spent.
VMAT; IMRT; Stage III lung cancer; Automated inverse planning
Conformal and intensity modulated radiation therapies have the potential to preserve cognitive outcomes in children with ependymoma; however, functional behavior remains uninvestigated. This longitudinal investigation prospectively examined intelligence quotient (IQ) and adaptive functioning during the first 5 years after irradiation in children diagnosed with ependymoma.
Methods and Materials
The study cohort consisted of 123 children with intracranial ependymoma. Mean age at irradiation was 4.60 years (95% confidence interval [CI], 3.85–5.35). Serial neurocognitive evaluations, including an age-appropriate IQ measure and the Vineland Adaptive Behavior Scales (VABS), were completed before irradiation, 6 months after treatment, and annually for 5 years. A total of 579 neurocognitive evaluations were included in these analyses.
Baseline IQ and VABS were below normative means (P<.05), although within the average range. Linear mixed models revealed stable IQ and VABS across the follow-up period, except for the VABS Communication Index, which declined significantly (P=.015). Annual change in IQ (−.04 points) did not correlate with annual change in VABS (−.90 to +.44 points). Clinical factors associated with poorer baseline performance (P<.05) included preirradiation chemotherapy, cerebrospinal fluid shunt placement, number and extent of surgical resections, and younger age at treatment. No clinical factors significantly affected the rate of change in scores.
Conformal and intensity modulated radiation therapies provided relative sparing of functional outcomes including IQ and adaptive behaviors, even in very young children. Communication skills remained vulnerable and should be the target of preventive and rehabilitative interventions.
To assess visual outcome prospectively after conformal radiation therapy (CRT) in children with optic pathway glioma.
Methods and Materials
We used CRT to treat optic pathway glioma in 20 children (median age 9.3 years) between July 1997 and January 2002. We assessed changes in visual acuity using the logarithm of the minimal angle of resolution after CRT (54 Gy) with a median follow-up of 24 months. We included in the study children who underwent chemotherapy (8 patients) or resection (9 patients) before CRT.
Surgery played a major role in determining baseline (pre-CRT) visual acuity (better eye: P=.0431; worse eye: P=.0032). The visual acuity in the worse eye was diminished at baseline (borderline significant) with administration of chemotherapy before CRT (P=.0726) and progression of disease prior to receiving CRT (P=.0220). In the worse eye, improvement in visual acuity was observed in patients who did not receive chemotherapy before CRT (P=.0289).
Children with optic pathway glioma initially treated with chemotherapy prior to receiving radiation therapy have decreased visual acuity compared with those who receive primary radiation therapy. Limited surgery before radiation therapy may have a role in preserving visual acuity.
Vision; Pediatrics; Glioma; Radiotherapy
To characterize the effect of a prostate-rectum spacer on dose to rectum during external beam radiotherapy for prostate cancer, and to assess for factors correlated with rectal dose reduction.
Materials and methods
Fifty-two patients at 4 institutions were enrolled onto a prospective pilot clinical trial. Patients underwent baseline scans, then were injected with perirectal spacing hydrogel and re-scanned. IMRT plans were created on both scans for comparison. Objectives were to establish rates of creation of ≥7.5mm of prostate-rectal separation, and decrease in rectal V70 of ≥25%. Multiple regression analysis was performed to evaluate associations between pre- vs. post-injection changes in rectal V70 and changes in plan conformity, rectal volume, bladder volume, bladder V70, PTV volume, as well as post-injection mid-gland separation, gel volume, gel thickness, length of PTV/gel contact, or gel left-to-right symmetry.
Hydrogel resulted in ≥ 7.5mm prostate-rectal separation in 95.8% of patients; 95.7% had decreased rectal V70 of ≥ 25%, with mean reduction of 8.0 Gy. There were no significant differences in pre- and post-injection prostate, PTV, rectal, and bladder volumes. Plan conformities were significantly different pre- vs. post-injection (P = 0.02); plans with worse conformity indexes post-injection compared to pre-injection (n=13) still had improvements in rectal V70. In multiple regression analysis, greater post-injection reduction in V70 was associated with decreased relative post-injection plan conformity (P=0.01). Reductions in V70 did not significantly vary by institution, despite significant inter-institutional variations in plan conformity. There were no significant relationships between reduction in V70 and the other characteristics analyzed.
Injection of hydrogel into prostate-rectal interface resulted in dose reductions to rectum for > 90% of patients treated. Rectal sparing was statistically significant across a range of 10–75 Gy, and was demonstrated within the presence of significant inter-institutional variability in plan conformity, target definitions, and injection results.