International Journal of Radiation Oncology * Biology * Physics

Issue Highlights

2012-03-01

S. K. Yi, W. H. Hall, M. Mathai, A. B. Dublin, V. Gupta, J. A. Purdy, and A. M. Chen In this study the Radiation Therapy Oncology Group-endorsed brachial plexus contouring atlas was used to guide three radiation oncologists to independently delineate this particular structure on treatment planning CT scans from representative head-and-neck cancer patients undergoing IMRT. Inter-observer differences were remarkably small and thus this atlas appears to provide a consistent set of guidelines for contouring with essentially no learning curve.

Oncology Scan - March 1, 2012

Arno J. Mundt — 2012-03-01

Dueñas-González A, Zarbá JJ, Patel F, et al. Phase III, Open-Label, Randomized Study Comparing Concurrent Gemcitabine Plus Cisplatin and Radiation Followed by Adjuvant Gemcitabine and Cisplatin Versus Concurrent Cisplatin and Radiation in Patients with Stage IIB to IVA Carcinoma of the Cervix. J Clin Oncol 2011;29:1679-1685

Are the Results of RTOG 0617 Mysterious?

James D. Cox — 2012-03-01

On June 17, 2011, two of the four arms in the Radiation Therapy Oncology Group (RTOG) 0617 protocol were closed to accrual when a planned interim analysis showed that the higher radiation dose being tested, 74 Gy, could not produce an overall survival benefit compared with the lower, standard dose of 60 Gy . This four-arm study was designed to test radiation with carboplatin and paclitaxel, with or without cetuximab, for Stage III non–small-cell lung cancer (NSCLC). Survival was compared between the two 74-Gy groups and the two 60-Gy groups, and overall survival was found to be better in the lower dose groups (1-year overall survival rate, 70.4% in the 74-Gy groups vs. 81% in the 60-Gy groups—both respectable rates for this stage of disease). However, even though 17 patients died in the 74-Gy arms compared with 7 in the 60-Gy arms, the toxicity rates were no different between the two dose groups. These findings are not only counterintuitive, they run counter to a large body of evidence showing that higher radiation doses lead to better tumor control at numerous sites. Deaths related to the effects on the normal lungs and perhaps the heart from high-dose three-dimensional conformal radiotherapy (3D-CRT) and intensity-modulated RT (IMRT) are the most likely explanation of the findings from the RTOG 0617. Considerable evidence, summarized below, supports the hypothesis that the pulmonary or cardiopulmonary effects of thoracic RT can contribute to death.

Adjuvant Versus Salvage Radiotherapy After Prostatectomy: The Apple Versus the Orange

Christopher R. King — 2012-03-01

The eradication of microscopic residual disease within the prostate bed after radical prostatectomy (RP) can potentially be achieved with the use of radiotherapy (RT) by two distinct strategies: in the salvage setting (SRT) at the time of a demonstrated biochemical recurrence, or in the adjuvant setting (ART) shortly after surgery, but in the absence of any measurable disease. These two competing strategies and the lack of data from randomized trials have created a longstanding dilemma: choosing adjuvant RT for all patients deemed at high risk, or waiting to deliver salvage RT only to those patients with known disease. How many patients does the ART strategy overtreat? Is the opportunity for cure lost or diminished in the “wait for detectable failure” strategy of SRT?

Radiotherapy for Liver Metastases: A Review of Evidence

2012-03-01

Over the past decade, there has been an increasing use of radiotherapy (RT) for the treatment of liver metastases. Most often, ablative doses are delivered to focal liver metastases with the goal of local control and ultimately improving survival. In contrast, low-dose whole-liver RT may be used for the palliation of symptomatic diffuse metastases. This review examines the available clinical data for both approaches. The review found that RT is effective both for local ablation of focal liver metastases and for palliation of patients with symptomatic liver metastases. However, there is a lack of a high level of evidence from randomized clinical trials.

Clinical Fundamentals for Radiation Oncologists

Kin-Sing Au — 2012-03-01

Clinical Fundamentals for Radiation Oncologists, an updated and expanded version of Clinical Fundamentals for Radiation Oncology Residents (2006) based on Dr. Murshed’s preparation for the board examination, is a concise book serving as an excellent source of information for a resident or a practicing radiation oncologist.

In Regard to “Thymidylate Synthase Gene Polymorphism Affects the Response to Preoperative 5-Fluorouracil Chemoradiation Therapy in Patients With Rectal Cancer” (Int J Radiat Oncol Biol Phys 2011;81:669–676)

2012-03-01

To the Editor: When preparing a manuscript addressing TS genetic polymorphisms in the context of neoadjuvant radiochemotherapy in patients with locally advanced rectal cancer, we read with great interest the study by Hur and colleagues . Of course, predictive markers for efficiency of the applied therapy regimen would be of high clinical value, which is documented by the high interest this issue has in the literature. In view of published data and our own data in this field, we would like to add some comments:

In Regard to “Breast Cancer Recurrent on Supraclavicular Node(s): What Is the Treatment?” (Int J Radiat Oncol Biol Phys 2011;80:1453–1457)

Stefano Pergolizzi, Anna Santacaterina — 2012-03-01

To the Editor: In a recent issue of this journal, Reddy et al. reported encouraging overall survival data after isolated supraclavicular nodal recurrence (ISNR) in breast cancer patients previously submitted to mastectomy and doxorubicin-based chemotherapy with or without irradiation. The prognosis of ISNR is generally poor: it has been shown that patients have a 5-year survival rate ranging between 5% and 35% . Reddy et al. reported that at the time of relapse the treatment was principally oriented to systemic therapy, whereas an “aggressive local approach” was delivered in only 6 patients, 3 of whom received radiation. In this retrospective analysis the authors observed an overall 3-year survival rate of 49%, with a 3-year distant metastasis–free survival rate of 40% in 47 patients with ISNR. Of these 47 patients, 23 had ISNR alone, and the remaining 24 had ISNR and other local–regional sites of recurrent disease. Analyzing the 23 patients with ISNR alone, the observed 5-year overall survival rate was 46%, with a 5-year distant metastasis–free survival rate of 30%. These are important observations because the implication is that “local therapy” (surgery and/or radiotherapy) can be omitted in a large percentage of patients with ISNR. However, this observation is in conflict both with most of literature data on this issue and the authors’ discussion . In fact, both prospective and retrospective studies seem to demonstrate that the combined use of irradiation and chemo/hormonal therapy ameliorates the clinical outcome in this rare but important clinical scenario, and multidisciplinary management is recommended . It is noteworthy that in the study by Reddy et al. the pathologic confirmation (cytology or biopsy) of recurrent disease on supraclavicular node/s is unreported. We think it is important for the authors to comment on these issues and perhaps reply within the context of this journal.

In Reply to Drs. Pergolizzi and Santacaterina

Jay P. Reddy, Wendy A. Woodward — 2012-03-01

To the Editor: We appreciate the comments made by Drs. Pergolizzi and Santacaterina on our recent report on patient outcomes in the setting of isolated supraclavicular nodal (SCV) recurrence after mastectomy and doxorubicin-based chemotherapy. Their commentary is thoughtful and well articulated, and we appreciate the opportunity to respond.

Validating the RTOG-Endorsed Brachial Plexus Contouring Atlas: An Evaluation of Reproducibility Among Patients Treated by Intensity-Modulated Radiotherapy for Head-and-Neck Cancer

2011-05-02

Purpose: To evaluate interobserver variability for contouring the brachial plexus as an organ-at-risk (OAR) and to analyze its potential dosimetric consequences in patients treated with intensity-modulated radiotherapy (IMRT) for head-and-neck cancer.Methods and Materials: Using the Radiation Therapy Oncology Group (RTOG)-endorsed brachial plexus contouring atlas, three radiation oncologists independently delineated the OAR on treatment planning computed-tomography (CT) axial scans from 5 representative patients undergoing IMRT to a prescribed dose of 70 Gy for head-and-neck cancer. Dose-volume histograms for the brachial plexus were calculated, and interobserver differences were quantified by comparing various dosimetric statistics. Qualitative analysis was performed by visually assessing the overlapping contours on a single beam’s eye view.Results: Brachial plexus volumes for the 5 patients across observers were 26 cc (18–35 cc), 25 cc (21–30 cc), 29 cc (28–32 cc), 29 cc (23–38 cc), and 29 cc (23–34 cc). On qualitative analysis, minimal variability existed except at the inferolateral portion of the OAR, where slight discrepancies were noted among the physicians. Maximum doses to the brachial plexus ranged from 71.6 to 72.6 Gy, 75.2 to 75.8 Gy, 69.1 to 71.0 Gy, 76.4 to 76.9 Gy, and 70.6 to 71.4 Gy. Respective volumes receiving doses greater than 60 Gy (V60) were 8.6 to 10.9 cc, 6.2 to 8.1 cc, 8.2 to 11.6 cc, 8.3 to 10.5 cc, and 5.6 to 9.8 cc.Conclusion: The RTOG-endorsed brachial plexus atlas provides a consistent set of guidelines for contouring this OAR with essentially no learning curve. Adoption of these contouring guidelines in the clinical setting is encouraged.

Standardized Total Average Toxicity Score: A Scale- and Grade-Independent Measure of Late Radiotherapy Toxicity to Facilitate Pooling of Data From Different Studies

2011-05-23

Purpose: The search for clinical and biologic biomarkers associated with late radiotherapy toxicity is hindered by the use of multiple and different endpoints from a variety of scoring systems, hampering comparisons across studies and pooling of data. We propose a novel metric, the Standardized Total Average Toxicity (STAT) score, to try to overcome these difficulties.Methods and Materials: STAT scores were derived for 1010 patients from the Cambridge breast intensity-modulated radiotherapy trial and 493 women from the University Hospitals of Leicester. The sensitivity of the STAT score to detect differences between patient groups, stratified by factors known to influence late toxicity, was compared with that of individual endpoints. Analysis of residuals was used to quantify the effect of these covariates.Results: In the Cambridge cohort, STAT scores detected differences (p < 0.00005) between patients attributable to breast volume, surgical specimen weight, dosimetry, acute toxicity, radiation boost to tumor bed, postoperative infection, and smoking (p < 0.0002), with no loss of sensitivity over individual toxicity endpoints. Diabetes (p = 0.017), poor postoperative surgical cosmesis (p = 0.0036), use of chemotherapy (p = 0.0054), and increasing age (p = 0.041) were also associated with increased STAT score. When the Cambridge and Leicester datasets were combined, STAT was associated with smoking status (p < 0.00005), diabetes (p = 0.041), chemotherapy (p = 0.0008), and radiotherapy boost (p = 0.0001). STAT was independent of the toxicity scale used and was able to deal with missing data. There were correlations between residuals of the STAT score obtained using different toxicity scales (r > 0.86, p < 0.00005 for both datasets).Conclusions: The STAT score may be used to facilitate the analysis of overall late radiation toxicity, from multiple trials or centers, in studies of possible genetic and nongenetic determinants of radiotherapy toxicity.

Effects of Irradiation on Brain Vasculature Using an In Situ Tumor Model

2011-12-23

Purpose: Damage to normal tissue is a limiting factor in clinical radiotherapy (RT). We tested the hypothesis that the presence of tumor alters the response of normal tissues to irradiation using a rat in situ brain tumor model.Methods and Materials: Intravital microscopy was used with a rat cranial window to assess the in situ effect of rat C6 glioma on peritumoral tissue with and without RT. The RT regimen included 40 Gy at 8 Gy/day starting Day 5 after tumor implant. Endpoints included blood–brain barrier permeability, clearance index, leukocyte-endothelial interactions and staining for vascular endothelial growth factor (VEGF) glial fibrillary acidic protein, and apoptosis. To characterize the system response to RT, animal survival and tumor surface area and volume were measured. Sham experiments were performed on similar animals implanted with basement membrane matrix absent of tumor cells.Results: The presence of tumor alone increases permeability but has little effect on leukocyte–endothelial interactions and astrogliosis. Radiation alone increases tissue permeability, leukocyte-endothelial interactions, and astrogliosis. The highest levels of permeability and cell adhesion were seen in the model that combined tumor and irradiation; however, the presence of tumor appeared to reduce the volume of rolling leukocytes. Unirradiated tumor and peritumoral tissue had poor clearance. Irradiated tumor and peritumoral tissue had a similar clearance index to irradiated and unirradiated sham-implanted animals. Radiation reduces the presence of VEGF in peritumoral normal tissues but did not affect the amount of apoptosis in the normal tissue. Apoptosis was identified in the tumor tissue with and without radiation.Conclusions: We developed a novel approach to demonstrate that the presence of the tumor in a rat intracranial model alters the response of normal tissues to irradiation.

A Prolonged Time Interval Between Trauma and Prophylactic Radiation Therapy Significantly Increases the Risk of Heterotopic Ossification

2011-10-21

Purpose: To ascertain whether the time from injury to prophylactic radiation therapy (RT) influences the rate of heterotopic ossification (HO) after operative treatment of displaced acetabular fractures.Methods and Materials: This is a single-institution, retrospective analysis of patients referred for RT for the prevention of HO. Between January 2000 and January 2009, 585 patients with displaced acetabular fractures were treated surgically followed by RT for HO prevention. We analyzed the effect of time from injury on prevention of HO by RT. In all patients, 700 cGy was prescribed in a single fraction and delivered within 72 hours postsurgery. The patients were stratified into five groups according to time interval (in days) from the date of their accident to the date of RT: Groups A ≤3, B ≤7, C ≤14, D ≤21, and E >21days.Results: Of the 585 patients with displaced acetabular fractures treated with RT, (18%) 106 patients developed HO within the irradiated field. The risk of HO after RT increased from 10% for RT delivered ≤3 days to 92% for treatment delivered >21 days after the initial injury. Wilcoxon test showed a significant correlation between the risk of HO and the length of time from injury to RT (p < 0.0001). Chi-square test and multiple logistic regression analysis showed no significant association between all other factors and the risk of HO (race, gender, cause and type of fracture, surgical approach, or the use of indomethacin).Conclusions: Our data suggest that there is higher incidence and risk of HO if prophylactic RT is significantly delayed after a displaced acetabular fracture. Thus, RT should be administered as early as clinically possible after the trauma. Patients undergoing RT >3 weeks from their displaced acetabular fracture should be informed of the higher risk (>90%) of developing HO despite prophylaxis.

Risk of Carotid Blowout After Reirradiation of the Head and Neck: A Systematic Review

Mark W. McDonald, Michael G. Moore, Peter A.S. Johnstone — 2011-05-06

Purpose: Carotid blowout (CB) is a rare but frequently fatal complication of head-and-neck (H&N) cancer or its treatment. We sought to determine the reported rate of CB in patients receiving salvage reirradiation for H&N cancer.Methods and Materials: A literature search identified 27 published articles on H&N reirradiation involving 1554 patients, and a pooled analysis was performed to determine the rate of CB. Treatment parameters, including prior radiation dose, interval from prior radiation, dose and fractionation of reirradiation, use of salvage surgery, and chemotherapy, were abstracted and summarized. The cumulative risk of CB was compared between groups using Fisher’s exact test.Results: Among 1554 patients receiving salvage H&N reirradiation, there were 41 reported CBs, for a rate of 2.6%; 76% were fatal. In patients treated in a continuous course with 1.8–2-Gy daily fractions or 1.2-Gy twice-daily fractions, 36% of whom received concurrent chemotherapy, the rate of CB was 1.3%, compared with 4.5% in patients treated with 1.5 Gy twice daily in alternating weeks or with delayed accelerated hyperfractionation, all of whom received concurrent chemotherapy (p = 0.002). There was no statistically significant difference in the rate of CB between patients treated with or without concurrent chemotherapy, or between patients treated with or without salvage surgery before reirradiation.Conclusion: Carotid blowout is an infrequent but serious complication of salvage reirradiation for H&N cancer. The rate of CB was lower among patients treated with conventional or hyperfractionated schedules compared with regimens of accelerated hyperfractionation, though heterogeneous patient populations and treatment parameters preclude definite conclusions. Given the high mortality rate of CB, discussion of the risk of CB is an important component of informed consent for salvage reirradiation.

Prognostic Value of Prevertebral Space Involvement in Nasopharyngeal Carcinoma Based on Intensity-Modulated Radiotherapy

2011-08-23

Purpose: To investigate the prognostic significance of prevertebral space involvement (PSI) in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT).Methods and Materials: A retrospective review of data from 506 biopsy-proven, nonmetastatic NPCs was performed. Patients underwent magnetic resonance imaging examinations and received IMRT as their primary treatment.Results: In this series, 161 NPC patients (31.8%) had PSI. Parapharyngeal space (p < 0.001), skull base (p < 0.001), and paranasal sinuses (p = 0.009) were associated with PSI after multivariate analysis. The 4-year overall survival (OS), local relapse-free survival (LRFS), distant metastasis–free survival (DMFS) for NPC patients with and without PSI was 69.1% and 89.2% (p < 0.0001), 83.9% and 96.4% (p < 0.0001), and 71.6% and 89.6% (p < 0.0001), respectively. Multivariate analysis identified PSI as an independent negative prognostic factor for both OS (HR = 1.478–4.380; p = 0.001) and DMFS (HR = 1.389–4.174; p = 0.002). Patients with PSI had similar survival rates in OS and DMFS (p = 0.241 and p = 0.493, respectively) to that of T4 disease, while the differences between PSI and T3 disease in both OS and DMFS were distinctly significant (p = 0.029 and p = 0.029, respectively).Conclusions: For NPC patients treated with IMRT, PSI was found to be an independent prognostic factor for both OS and DMFS. It seems reasonable that PSI should be classified as a T4 disease on the basis of the current American Joint Committee on Cancer staging classification criteria.

Diffusion-Weighted Magnetic Resonance Imaging Early After Chemoradiotherapy to Monitor Treatment Response in Head-and-Neck Squamous Cell Carcinoma

2011-04-21

Purpose: To evaluate diffusion-weighted imaging (DWI) for assessment of treatment response in head and neck squamous cell carcinoma (HNSCC) three weeks after the end of chemoradiotherapy (CRT).Methods and Materials: Twenty-nine patients with HNSCC underwent magnetic resonance imaging (MRI) prior to and 3 weeks after CRT, including T2-weighted and pre- and postcontrast T1-weighted sequences and an echo-planar DWI sequence with six b values (0 to 1,000 s/mm2), from which the apparent diffusion coefficient (ADC) was calculated. ADC changes 3 weeks posttreatment compared to baseline (∆ADC) between responding and nonresponding primary lesions and adenopathies were correlated with 2 years locoregional control and compared with a Mann-Whitney test. In a blinded manner, the ∆ADC was compared to conventional MRI 3 weeks post-CRT and the routinely implemented CT, on average 3 months post-CRT, which used size-related and morphological criteria. Positive and negative predictive values (PPV and NPV, respectively) were compared between the ∆ADC and anatomical imaging.Results: The ∆ADC of lesions with later tumor recurrence was significantly lower than lesions with complete remission for both primary lesions (−2.3% ± 0.3% vs. 80% ± 41%; p < 0.0001) and adenopathies (19.9% ± 32% vs. 63% ± 36%; p = 0.003). The ∆ADC showed a PPV of 89% and an NPV of 100% for primary lesions and a PPV of 70% and an NPV of 96% for adenopathies per neck side. DWI improved PPV and NPV compared to anatomical imaging.Conclusion: DWI with the ∆ADC 3 weeks after concluding CRT for HNSCC allows for early assessment of treatment response.

Treatment Planning Constraints to Avoid Xerostomia in Head-and-Neck Radiotherapy: An Independent Test of QUANTEC Criteria Using a Prospectively Collected Dataset

2011-06-02

Purpose: The severe reduction of salivary function (xerostomia) is a common complication after radiation therapy for head-and-neck cancer. Consequently, guidelines to ensure adequate function based on parotid gland tolerance dose–volume parameters have been suggested by the QUANTEC group and by Ortholan et al. We perform a validation test of these guidelines against a prospectively collected dataset and compared with a previously published dataset.Methods and Materials: Whole-mouth stimulated salivary flow data from 66 head-and-neck cancer patients treated with radiotherapy at the British Columbia Cancer Agency (BCCA) were measured, and treatment planning data were abstracted. Flow measurements were collected from 50 patients at 3 months, and 60 patients at 12-month follow-up. Previously published data from a second institution, Washington University in St. Louis (WUSTL), were used for comparison. A logistic model was used to describe the incidence of Grade 4 xerostomia as a function of the mean dose of the spared parotid gland. The rate of correctly predicting the lack of xerostomia (negative predictive value [NPV]) was computed for both the QUANTEC constraints and Ortholan et al. recommendation to constrain the total volume of both glands receiving more than 40 Gy to less than 33%.Results: Both datasets showed a rate of xerostomia of less than 20% when the mean dose to the least-irradiated parotid gland is kept to less than 20 Gy. Logistic model parameters for the incidence of xerostomia at 12 months after therapy, based on the least-irradiated gland, were D50 = 32.4 Gy and and γ = 0.97. NPVs for QUANTEC guideline were 94% (BCCA data), and 90% (WUSTL data). For Ortholan et al. guideline NPVs were 85% (BCCA) and 86% (WUSTL).Conclusion: These data confirm that the QUANTEC guideline effectively avoids xerostomia, and this is somewhat more effective than constraints on the volume receiving more than 40 Gy.

Dynamic Contrast-Enhanced MRI in Head-and-Neck Cancer: The Impact of Region of Interest Selection on the Intra- and Interpatient Variability of Pharmacokinetic Parameters

2011-10-10

Purpose: Dynamic contrast–enhanced (DCE) MRI-extracted parameters measure tumor microvascular physiology and are usually calculated from an intratumor region of interest (ROI). Optimal ROI delineation is not established. The valid clinical use of DCE-MRI requires that the variation for any given parameter measured within a tumor be less than that observed between tumors in different patients. This work evaluates the impact of tumor ROI selection on the assessment of intra- and interpatient variability.Method and Materials: Head and neck cancer patients received initial targeted therapy (TT) treatment with erlotinib and/or bevacizumab, followed by radiotherapy and concurrent cisplatin with synchronous TT. DCE-MRI data from Baseline and the end of the TT regimen (Lead-In) were analyzed to generate the vascular transfer function (Ktrans), the extracellular volume fraction (ve), and the initial area under the concentration time curve (iAUC1 min). Four ROI sampling strategies were used: whole tumor or lymph node (Whole), the slice containing the most enhancing voxels (SliceMax), three slices centered in SliceMax (Partial), and the 5% most enhancing contiguous voxels within SliceMax (95Max). The average coefficient of variation (aCV) was calculated to establish intrapatient variability among ROI sets and interpatient variability for each ROI type. The average ratio between each intrapatient CV and the interpatient CV was calculated (aRCV).Results: Baseline primary/nodes aRCVs for different ROIs not including 95Max were, for all three MR parameters, in the range of 0.14–0.24, with Lead-In values between 0.09 and 0.2, meaning a low intrapatient vs. interpatient variation. For 95Max, intrapatient CVs approximated interpatient CVs, meaning similar data dispersion and higher aRCVs (0.6–1.27 for baseline) and 0.54–0.95 for Lead-In.Conclusion: Distinction between different patient’s primary tumors and/or nodes cannot be made using 95Max ROIs. The other three strategies are viable and equivalent for using DCE-MRI to measure head and neck cancer physiology.

Quantitation of Human Papillomavirus DNA in Plasma of Oropharyngeal Carcinoma Patients

2011-10-10

Purpose: To determine whether human papillomavirus (HPV) DNA can be detected in the plasma of patients with HPV-positive oropharyngeal carcinoma (OPC) and to monitor its temporal change during radiotherapy.Methods and Materials: We used polymerase chain reaction to detect HPV DNA in the culture media of HPV-positive SCC90 and VU147T cells and the plasma of SCC90 and HeLa tumor-bearing mice, non-tumor-bearing controls, and those with HPV-negative tumors. We used real-time quantitative polymerase chain reaction to quantify the plasma HPV DNA in 40 HPV-positive OPC, 24 HPV-negative head-and-neck cancer patients and 10 non-cancer volunteers. The tumor HPV status was confirmed by p16INK4a staining and HPV16/18 polymerase chain reaction or HPV in situ hybridization. A total of 14 patients had serial plasma samples for HPV DNA quantification during radiotherapy.Results: HPV DNA was detectable in the plasma samples of SCC90- and HeLa-bearing mice but not in the controls. It was detected in 65% of the pretreatment plasma samples from HPV-positive OPC patients using E6/7 quantitative polymerase chain reaction. None of the HPV-negative head-and-neck cancer patients or non-cancer controls had detectable HPV DNA. The pretreatment plasma HPV DNA copy number correlated significantly with the nodal metabolic tumor volume (assessed using 18F-deoxyglucose positron emission tomography). The serial measurements in 14 patients showed a rapid decline in HPV DNA that had become undetectable at radiotherapy completion. In 3 patients, the HPV DNA level had increased to a discernable level at metastasis.Conclusions: Xenograft studies indicated that plasma HPV DNA is released from HPV-positive tumors. Circulating HPV DNA was detectable in most HPV-positive OPC patients. Thus, plasma HPV DNA might be a valuable tool for identifying relapse.

Baseline Serum Lactate Dehydrogenase Levels for Patients Treated With Intensity-Modulated Radiotherapy for Nasopharyngeal Carcinoma: A Predictor of Poor Prognosis and Subsequent Liver Metastasis

2011-10-13

Purpose: To evaluate the prognostic value of baseline serum lactate dehydrogenase (LDH) levels in patients with nasopharyngeal carcinoma (NPC) treated with intensity-modulated radiotherapy (IMRT).Methods and Materials: Cases of NPC (n = 465) that involved treatment with IMRT with or without chemotherapy were retrospectively analyzed.Results: The mean (±SD) and median baseline serum LDH levels for this cohort were 172.77 ± 2.28 and 164.00 IU/L, respectively. Levels of LDH were significantly elevated in patients with locoregionally advanced disease (p = 0.016). Elevated LDH levels were identified as a prognostic factor for rates of overall survival (OS), disease-free survival (DFS), and distant metastasis-free survival (DMFS), with p values <0.001 in the univariate analysis and p < 0.001, p = 0.004, and p = 0.003, respectively, in the multivariate analysis. Correspondingly, the prognostic impact of patient LDH levels was found to be statistically significant for rates of OS, DFS, and DMFS (p = 0.028, 0.024, and 0.020, respectively). For patients who experienced subsequent liver failure after treatment, markedly higher pretreatment serum LDH levels were detected compared with patients experiencing distant metastasis events at other sites (p = 0.032).Conclusions: Elevated baseline LDH levels are associated with clinically advanced disease and are a poor prognosticator for OS, DFS, and DMFS for NPC patients. These results suggest that elevated serum levels of LDH should be considered when evaluating treatment options.

Prediction of Neck Dissection Requirement After Definitive Radiotherapy for Head-and-Neck Squamous Cell Carcinoma

2012-03-01

Background: This analysis was undertaken to assess the need for planned neck dissection in patients with a complete response (CR) of involved nodes after irradiation and to determine the benefit of a neck dissection in those with less than CR by tumor site.Methods: Our cohort included 880 patients with T1-4, N1-3M0 squamous cell carcinoma of the oropharynx, larynx, or hypopharynx who received treatment between 1994 and 2004. Survival curves were calculated by the Kaplan-Meier Method, comparisons of rates with the log–rank test and prognostic factors by Cox's proportional hazard model.Results: Nodal CR occurred in 377 (43%) patients, of whom 365 patients did not undergo nodal dissection. The 5-year actuarial regional control rate of patients with CR was 92%. Two hundred sixty-eight of the remaining patients (53%) underwent neck dissections. The 5-year actuarial regional control rate for patients without a CR was 84%. Those who had a neck dissection fared better with 5-year actuarial regional control rates of 90% and 76% for those operated and those not operated (p < 0.001). Variables associated with poorer regional control rates included higher T and N stage, non-oropharynx cancers, non-CR, both clinical and pathological.Conclusions: With 92% 5-year neck control rate without neck dissection after CR, there is little justification for systematic neck dissection. The addition of a neck dissection resulted in higher neck control after partial response though patients with viable tumor on pathology specimens had poorer outcomes. The identification of that subgroup that benefits from additional treatment remains a challenge.

Monitoring Dosimetric Impact of Weight Loss With Kilovoltage (KV) Cone Beam CT (CBCT) During Parotid-Sparing IMRT and Concurrent Chemotherapy

2011-12-23

Purpose: Parotid-sparing head-and-neck intensity-modulated radiotherapy (IMRT) can reduce long-term xerostomia. However, patients frequently experience weight loss and tumor shrinkage during treatment. We evaluate the use of kilovoltage (kV) cone beam computed tomography (CBCT) for dose monitoring and examine if the dosimetric impact of such changes on the parotid and critical neural structures warrants replanning during treatment.Methods and materials: Ten patients with locally advanced oropharyngeal cancer were treated with contralateral parotid-sparing IMRT concurrently with platinum-based chemotherapy. Mean doses of 65 Gy and 54 Gy were delivered to clinical target volume (CTV)1 and CTV2, respectively, in 30 daily fractions. CBCT was prospectively acquired weekly. Each CBCT was coregistered with the planned isocenter. The spinal cord, brainstem, parotids, larynx, and oral cavity were outlined on each CBCT. Dose distributions were recalculated on the CBCT after correcting the gray scale to provide accurate Hounsfield calibration, using the original IMRT plan configuration.Results: Planned contralateral parotid mean doses were not significantly different to those delivered during treatment (p > 0.1). Ipsilateral and contralateral parotids showed a mean reduction in volume of 29.7% and 28.4%, respectively. There was no significant difference between planned and delivered maximum dose to the brainstem (p = 0.6) or spinal cord (p = 0.2), mean dose to larynx (p = 0.5) and oral cavity (p = 0.8). End-of-treatment mean weight loss was 7.5 kg (8.8% of baseline weight). Despite a ≥10% weight loss in 5 patients, there was no significant dosimetric change affecting the contralateral parotid and neural structures.Conclusions: Although patient weight loss and parotid volume shrinkage was observed, overall, there was no significant excess dose to the organs at risk. No replanning was felt necessary for this patient cohort, but a larger patient sample will be investigated to further confirm these results. Nevertheless, kilovoltage CBCT is a valuable tool for patient setup verification and monitoring of dosimetric variation during radiotherapy.

Mild Toxicity and Favorable Prognosis of High–Dose and Extended Involved-Field Intensity-Modulated Radiotherapy for Patients With Early-Stage Nasal NK/T-Cell Lymphoma

2011-04-21

Purpose: The value of intensity-modulated radiotherapy (IMRT) for early-stage nasal NK/T-cell lymphoma has not been previously reported. The aim of the present study was to assess the dosimetric parameters, toxicity, and treatment outcomes of patients with nasal NK/T-cell lymphoma.Methods and Materials: Between 2003 and 2008, 42 patients with early-stage nasal NK/T-cell lymphoma underwent definitive high-dose and extended involved-field IMRT with or without combination chemotherapy. The median radiation dose to the primary tumor was 50 Gy. The dose–volume histograms of the target volume and critical normal structures were evaluated in all patients. The locoregional control, overall survival, and progression-free survival were calculated using the Kaplan-Meier method.Results: The average mean dose delivered to the planning target volume was 55.5 Gy. Only 1.3% and 2.5% of the planning target volume received <90% and 95% of the prescribed dose, respectively, indicating excellent planning target volume coverage. The mean dose and average dose to the parotid glands was 15 Gy and 14 Gy, respectively. With a median follow-up time of 27 months, the 2-year locoregional control, overall survival, and progression-free survivalrate was 93%, 78%, and 74%, respectively. No Grade 4 or 5 acute or late toxicity was reported.Conclusions: High-dose and extended involved-field IMRT for patients with early-stage nasal NK/T-cell lymphoma showed favorable locoregional control, overall survival, and progression-free survival, with mild toxicity. The dose constraints of IMRT for the parotid glands can be limited to <20 Gy in these patients.

Outcomes of Patients With Non-Hodgkin's Lymphoma Treated With Bexxar With or Without External-Beam Radiotherapy

2011-05-12

Purpose: To compare the efficacy and toxicity of external-beam radiotherapy (EBRT) to sites of bulky lymphadenopathy in patients with chemotherapy-refractory low-grade non-Hodgkin’s lymphoma (NHL) immediately before receiving Bexxar (tositumomab and 131I) vs. in patients receiving Bexxar alone for nonbulky disease.Methods and Materials: Nineteen patients with chemotherapy-refractory NHL were treated with Bexxar at our institution (University of Florida, Gainesville, FL) from 2005 to 2008. Seventeen patients had Grade 1–2 follicular lymphoma. Ten patients received a median of 20 Gy in 10 fractions to the areas of clinical involvement, immediately followed by Bexxar (EBRT + Bexxar); 9 patients received Bexxar alone. The median tumor sizes before EBRT + Bexxar and Bexxar alone were 4.8 cm and 3.3 cm, respectively. All 5 patients with a tumor diameter >5 cm were treated with EBRT + Bexxar. A univariate analysis of prognostic factors for progression-free survival (PFS) was performed.Results: The median follow-up was 2.3 years for all patients and 3.1 years for 12 patients alive at last follow-up. Of all patients, 79% had a partial or complete response; 4 of the 8 responders in the EBRT + Bexxar group achieved a durable response of over 2 years, including 3 of the 5 with tumors >5 cm. Three of 9 patients treated with Bexxar alone achieved a durable response over 2 years. Actuarial estimates of 3-year overall survival and PFS for EBRT + Bexxar and Bexxar alone were 69% and 38% and 62% and 33%, respectively. The median time to recurrence after EBRT + Bexxar and Bexxar alone was 9 months. Having fewer than 4 involved lymph-node regions was associated with superior PFS at 3 years (63% vs. 18%). There was no Grade 4 or 5 complications.Conclusions: Adding EBRT immediately before Bexxar produced PFS equivalent to that with Bexxar alone, despite bulkier disease. Hematologic toxicity was not worsened. EBRT combined with Bexxar adds a safe and effective therapeutic treatment for managing recurrent low-grade follicular NHL.

Multimodality Local Therapy for Retroperitoneal Sarcoma

2011-06-09

Purpose: Soft-tissue sarcomas of the retroperitoneum are rare tumors comprising less than 1% of all malignancies. Although surgery continues as the mainstay of treatment, the large size of these tumors coupled with their proximity to critical structures make resection with wide margins difficult to achieve. The role and timing of radiotherapy are controversial. This study updates our institutional experience using multimodality local therapy for resectable retroperitoneal sarcoma and identifies prognostic factors impacting disease control and survival.Methods and Materials: Between 1974 and 2007, 58 patients with nonmetastatic retroperitoneal sarcoma were treated with surgery and radiation at the University of Florida. The median age at radiotherapy was 57 years old (range, 18–80 years). Forty-two patients received preoperative radiotherapy and 16 received postoperative radiotherapy. Nineteen patients received 1.8 Gy once daily and 39 patients received 1.2 Gy twice daily. Variables analyzed for prognostic value included age, grade, kidney involvement, histology, de novo versus recurrent presentation, tumor diameter, margin status, radiotherapy sequencing (preoperative vs. postoperative), total radiation dose, fractionation scheme, and treatment era.Results: The 5-year overall survival, cause-specific survival, and local control rates were 49%, 58%, and 62%, respectively. Nearly two-thirds of disease failures involved a component of local progression. On multivariate analysis, only margin status was significantly associated with improved 5-year local control (85%, negative margins; 63%, microscopic positive margins; 0%, gross positive margins; p < 0.0001) and 5-year overall survival (64%, negative margins; 56%, microscopic positive margins; 13%, gross positive margins; p = 0.0012). Thirty-one Grade 3 or greater toxicities were observed in 22 patients, including two treatment-related deaths (3%).Conclusion: For retroperitoneal sarcoma, local control remains a challenge and combined-modality therapy may be associated with significant acute and late morbidity. Our patterns of failure data suggest that improvements in local control may translate into a survival benefit.

Supratentorial Neurometabolic Alterations in Pediatric Survivors of Posterior Fossa Tumors

Stefan M. Rueckriegel, Pablo Hernáiz Driever, Harald Bruhn — 2011-06-09

Purpose: Therapy and tumor-related effects such as hypoperfusion, internal hydrocephalus, chemotherapy, and irradiation lead to significant motor and cognitive sequelae in pediatric posterior fossa tumor survivors. A distinct proportion of those factors related to the resulting late effects is hitherto poorly understood. This study aimed at separating the effects of neurotoxic factors on central nervous system metabolism by using H-1 MR spectroscopy to quantify cerebral metabolite concentrations in these patients in comparison to those in age-matched healthy peers.Methods and Materials: Fifteen patients with World Health Organization (WHO) I pilocytic astrocytoma (PA) treated by resection only, 24 patients with WHO IV medulloblastoma (MB), who additionally received chemotherapy and craniospinal irradiation, and 43 healthy peers were investigated using single-volume H-1 MR spectroscopy of parietal white matter and gray matter.Results: Concentrations of N-acetylaspartate (NAA) were significantly decreased in white matter (p < 0.0001) and gray matter (p < 0.0001) of MB patients and in gray matter (p = 0.005) of PA patients, compared to healthy peers. Decreased creatine concentrations in parietal gray matter correlated significantly with older age at diagnosis in both patient groups (MB patients, p = 0.009, r = 0.52; PA patients, p = 0.006, r = 0.7). Longer time periods since diagnosis were associated with lower NAA levels in white matter of PA patients (p = 0.008, r = 0.66).Conclusions: Differently decreased NAA concentrations were observed in both PA and MB groups of posterior fossa tumor patients. We conclude that this reflects a disturbance of the neurometabolic steady state of normal-appearing brain tissue due to the tumor itself and to the impact of surgery in both patient groups. Further incremental decreases of metabolite concentrations in MB patients may point to additional harm caused by irradiation and chemotherapy. The stronger decrease of NAA in MB patients may correspond to the additional damage of combined irradiation and chemotherapy on neuroaxonal cell viability and number.

Proton Radiotherapy for Pediatric Ewing’s Sarcoma: Initial Clinical Outcomes

2011-08-19

Purpose: Proton radiotherapy (PT) has been prescribed similarly to photon radiotherapy to achieve comparable disease control rates at comparable doses. The chief advantage of protons in this setting is to reduce acute and late toxicities by decreasing the amount of normal tissue irradiated. We report the preliminary clinical outcomes including late effects on our pediatric Ewing’s sarcoma patients treated with PT at the Francis H. Burr Proton Therapy Center at Massachusetts General Hospital (Boston, MA).Methods and Materials: This was a retrospective review of the medical records of 30 children with Ewing’s sarcoma who were treated with PT between April 2003 and April 2009.Results: A total of 14 male and 16 female patients with tumors in several anatomic sites were treated with PT at a median age of 10 years. The median dose was 54 Gy (relative biological effectiveness) with a median follow-up of 38.4 months. The 3-year actuarial rates of event-free survival, local control, and overall survival were 60%, 86%, and 89%, respectively. PT was acutely well tolerated, with mostly mild-to-moderate skin reactions. At the time of writing, the only serious late effects have been four hematologic malignancies, which are known risks of topoisomerase and anthracyline exposure.Conclusions: Proton radiotherapy was well tolerated, with few adverse events. Longer follow-up is needed to more fully assess tumor control and late effects, but the preliminary results are encouraging.

Second Malignant Neoplasms in Digestive Organs After Childhood Cancer: A Cohort-Nested Case-Control Study

2012-03-01

Purpose: Cancers of the digestive system constitute a major risk for childhood cancer survivors treated with radiotherapy once they reach adulthood. The aim of this study was to determine therapy-related risk factors for the development of a second malignancy in the digestive organs (SMDO) after a childhood cancer.Methods and Materials: Among 4,568 2-year survivors of a childhood solid cancer diagnosed before 17 years of age at eight French and British centers, and among 25,120 patients diagnosed as having a malignant neoplasm before the age of 20 years, whose data were extracted from the Nordic Cancer Registries, we matched 58 case patients (41 men and 17 women) of SMDO and 167 controls, in their respective cohort, for sex, age at first cancer, calendar year of occurrence of the first cancer, and duration of follow-up. The radiation dose received at the site of each second malignancy and at the corresponding site of its matched control was estimated.Results: The risk of developing a SMDO was 9.7-fold higher in relation to the general populations in France and the United Kingdom. In the case-control study, a strong dose–response relationship was estimated, compared with that in survivors who had not received radiotherapy; the odds ratio was 5.2 (95% CI, 1.7–16.0) for local radiation doses between 10 and 29 Gy and 9.6 (95% CI, 2.6–35.2) for doses equal to or greater than 30 Gy. Chemotherapy was also found to increase the risk of developing SMDO.Conclusions: This study confirms that childhood cancer treatments strongly increase the risk of SMDO, which occur only after a very long latency period.

Curative Treatment of Stage I Non-Small-Cell Lung Cancer in Patients With Severe COPD: Stereotactic Radiotherapy Outcomes and Systematic Review

David Palma, Frank Lagerwaard, George Rodrigues, Cornelis Haasbeek, Suresh Senan — 2011-06-02

Objectives: Patients with severe chronic obstructive pulmonary disease (COPD) have a high risk of lung cancer and of postsurgical complications. We studied outcomes after stereotactic body radiotherapy (SBRT) in patients with severe COPD, as defined by Global Initiative for Chronic Obstructive Lung Disease (GOLD) criteria, and performed a systematic review of the literature on outcomes after SBRT or surgery in these patients.Methods: A single-institution cohort of 176 patients with COPD GOLD III-IV and Stage I non–small-cell lung cancer (NSCLC) treated with SBRT was evaluated. A systematic review identified studies reporting outcomes after SBRT or surgery for Stage I NSCLC in patients with GOLD III-IV or a predicted postoperative forced expiratory volume in 1 second (FEV1) of ≤40%.Results: In the single-institution cohort, median follow-up was 21 months and median overall survival (OS) was 32 months. Actuarial 3-year local control was 89%, and 1- and 3-year OS were 79% and 47%, respectively. COPD severity correlated with OS (p = 0.01). The systematic review identified four other studies (two surgical, two SBRT, n = 196 patients). SBRT studies were published more recently and included older patients than surgical studies. Mean 30-day mortality was 0% post-SBRT and 10% after surgery. Local or locoregional control was high (≥89%) after both treatments. Post-SBRT, actuarial OS was 79–95% at 1 year and 43–70% at 3 years. Postsurgical actuarial OS was 45–86% at 1 year and 31–66% at 3 years.Conclusions: SBRT and surgery differ in risk of 30-day mortality in patients with severe COPD. Despite the negative selection of SBRT patients, survival at 1 and 3 years is comparable between the two treatments.

Concurrent Hyperfractionated Radiation Therapy and Chemotherapy in Locally Advanced (Stage III) Non-Small-Cell Lung Cancer: Single Institution Experience With 600 Patients

Branislav Jeremić, Biljana Miličić, Slobodan Milisavljevic — 2011-06-02

Purpose: Our institutional experience with the use of hyperfractionated radiation therapy (RT) alone or concurrently with chemotherapy (RT-CHT) in Stage III non-small-cell lung cancer was reviewed.Methods and Materials: Three phase III and two phase II studies included a total of 600 patients. Hyperfractionated RT alone was given to 127 patients, and hyperfractionated RT-CHT was given to 473 patients. RT doses were 64.8 Gy and 69.6 Gy (using 1.2 Gy twice daily) and 67.6 Gy (using 1.3 Gy twice daily). CHT consisted of concurrent administration of carboplatin and etoposide to 409 patients and concurrent administration of carboplatin and paclitaxel to 64 patients.Results: The median survival times were 19 months, 21 months, and 12 months for all, RT-CHT, and RT-only patients, respectively. The survival difference between the RT-CHT and RT group was significant (p < 0.0001). Four-year rates of local progression-free survival (LPFS) and distant metastasis-free survival (DMFS) were 29% and 35%, respectively, for the entire group. The RT-CHT group had significantly better LPFS rates than the RT group (31% for the RT-CHT group vs. 16% for the RT group; p = 0.0015) but not DMFS rates (36% for the RT-CHT group vs. 36% for the RT group, p = 0.0571). Acute high-grade esophagitis, pneumonitis, and hematological toxicities were seen most frequently and in 11%, 9%, and 12% of patients, respectively. Late high-grade esophageal and bronchopulmonary toxicity were each seen in 6% of patients.Conclusions: Compared to the majority of existing phase II and III studies, this study reconfirmed the excellent results achieved with concurrent RT-CHT, including low toxicity. Concurrent RT-CHT results in survival benefit primarily by increasing LPFS, not DMFS.

What Is the Best Way to Contour Lung Tumors on PET Scans? Multiobserver Validation of a Gradient-Based Method Using a NSCLC Digital PET Phantom

2011-04-29

Purpose: To evaluate the accuracy and consistency of a gradient-based positron emission tomography (PET) segmentation method, GRADIENT, compared with manual (MANUAL) and constant threshold (THRESHOLD) methods.Methods and Materials: Contouring accuracy was evaluated with sphere phantoms and clinically realistic Monte Carlo PET phantoms of the thorax. The sphere phantoms were 10–37 mm in diameter and were acquired at five institutions emulating clinical conditions. One institution also acquired a sphere phantom with multiple source-to-background ratios of 2:1, 5:1, 10:1, 20:1, and 70:1. One observer segmented (contoured) each sphere with GRADIENT and THRESHOLD from 25% to 50% at 5% increments. Subsequently, seven physicians segmented 31 lesions (7–264 mL) from 25 digital thorax phantoms using GRADIENT, THRESHOLD, and MANUAL.Results: For spheres <20 mm in diameter, GRADIENT was the most accurate with a mean absolute % error in diameter of 8.15% (10.2% SD) compared with 49.2% (51.1% SD) for 45% THRESHOLD (p < 0.005). For larger spheres, the methods were statistically equivalent. For varying source-to-background ratios, GRADIENT was the most accurate for spheres >20 mm (p < 0.065) and <20 mm (p < 0.015). For digital thorax phantoms, GRADIENT was the most accurate (p < 0.01), with a mean absolute % error in volume of 10.99% (11.9% SD), followed by 25% THRESHOLD at 17.5% (29.4% SD), and MANUAL at 19.5% (17.2% SD). GRADIENT had the least systematic bias, with a mean % error in volume of –0.05% (16.2% SD) compared with 25% THRESHOLD at –2.1% (34.2% SD) and MANUAL at –16.3% (20.2% SD; p value <0.01). Interobserver variability was reduced using GRADIENT compared with both 25% THRESHOLD and MANUAL (p value <0.01, Levene’s test).Conclusion: GRADIENT was the most accurate and consistent technique for target volume contouring. GRADIENT was also the most robust for varying imaging conditions. GRADIENT has the potential to play an important role for tumor delineation in radiation therapy planning and response assessment.

Dose Constraints to Prevent Radiation-Induced Brachial Plexopathy in Patients Treated for Lung Cancer

2012-03-01

Purpose: 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 dose tolerated by 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 multiatlas segmentation method combined with deformable image registration to delineate the brachial plexus on the original planning CT scans and scored plexopathy according to Common Terminology Criteria for Adverse Events version 4.03.Results: 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 (16%) had brachial plexopathy (8 patients [9%] had Grade 1, and 6 patients [7%] had Grade ≥2); median time to symptom onset was 6.5 months (range, 1.4–37.4 months). On multivariate analysis, receipt of a median brachial plexus dose of >69 Gy (odds ratio [OR] 10.091; 95% confidence interval [CI], 1.512–67.331; p = 0.005), a maximum dose of >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.Conclusions: 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 that allows 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 trials with high-dose radiation therapy for unresectable lung cancer.

Quantification of the Variability of Diaphragm Motion and Implications for Treatment Margin Construction

Simon Rit, Marcel van Herk, Lambert Zijp, Jan-Jakob Sonke — 2012-03-01

Purpose: To quantify the variability of diaphragm motion during free-breathing radiotherapy of lung patients and its effect on treatment margins to account for geometric uncertainties.Methods and Materials: Thirty-three lung cancer patients were analyzed. Each patient had 5–19 cone-beam scans acquired during different treatment fractions. The craniocaudal position of the diaphragm dome on the same side as the tumor was tracked over 2 min in the projection images, because it is both easily visible and a suitable surrogate to study the variability of the tumor motion and its impact on treatment margins. Intra-acquisition, inter-acquisition, and inter-patient variability of the respiratory cycles were quantified separately, as were the probability density functions (PDFs) of the diaphragm position over each cycle, each acquisition, and each patient. Asymmetric margins were simulated using each patient PDF and compared to symmetric margins computed from a margin recipe.Results: The peak-to-peak amplitude variability (1 SD) was 3.3 mm, 2.4 mm, and 6.1 mm for the intra-acquisition, inter-acquisition, and inter-patient variability, respectively. The average PDF of each cycle was similar to the sin4 function but the PDF of each acquisition was closer to a skew-normal distribution because of the motion variability. Despite large interfraction baseline variability, the PDF of each patient was generally asymmetric with a longer end-inhale tail because the end-exhale position was more stable than the end-inhale position. The asymmetry of the PDF required asymmetric margins around the time-averaged position to account for the position uncertainty but the average difference was 1.0 mm (range, 0.0–4.4 mm) for a sharp penumbra and an idealized online setup correction protocol.Conclusion: The respiratory motion is more irregular during the fractions than between the fractions. The PDF of the respiratory motion is asymmetrically distributed. Both the intra-acquisition variability and the PDF asymmetry have a limited impact on dose distributions and inferred margins. The use of a margin recipe to account for respiratory motion with an estimate of the average motion amplitude was adequate in almost all patients.

Usefulness of Positron Emission Tomography With Fluorine-18-Fluorodeoxyglucose in Predicting Treatment Response in Unresectable Hepatocellular Carcinoma Patients Treated With External Beam Radiotherapy

2011-05-12

Purpose: To assess the significance of the ratio between standardized uptake values (SUV) of tumor and normal liver tissue obtained from positron emission tomography with fluorine-18-fluorodeoxyglucose (FDG-PET) in predicting the response of hepatocellular carcinoma (HCC) patients treated with external beam radiotherapy (EBRT).Methods and Materials: We retrospectively analyzed 35 HCC patients who were treated with EBRT between January 2004 and June 2007. All patients underwent FDG-PET in which SUV values were obtained from tumor and normal liver tissues and were used to calculate the ratios (SUVTumor/SUVLiver). After FDG-PET, patients received liver treatment including concurrent chemoradiation, transarterial chemoembolization plus RT, or intraarterial chemotherapy plus RT. Using three-dimensional conformal RT, median dose of 45 Gy was delivered in conventional fractions. Patients underwent abdominal/pelvic CT 1 month after RT, and treatment responses were evaluated according to the Response Evaluation Criteria in Solid Tumors criteria.Results: Patients were divided into high-SUV ratio group (n = 20) and low-SUV ratio group (n = 15) according to SUV ratio at a cutoff value of 2.5. Objective responses consisting of either complete response (CR) or partial response (PR) were observed in 16 and 6 patients (46% vs. 17%, p = 0.015), respectively; median survivals after RT were 8 months and 5 months (p = 0.41) for the high-SUV ratio group and the low-SUV ratio group, respectively. Rates of intrahepatic metastases (9% vs. 11%, p = 0.39) and distant metastases (32% vs. 32%, p = 0.27) showed no significant difference between two groups.Conclusions: External beam RT for HCC patients with higher SUV ratios resulted in higher response rates than for patients with lower SUV ratios. Treatment of HCC with higher SUV ratios did not result in increased survival; high rates of intrahepatic and distant metastases in both SUV groups may have affected patient survival. SUV ratios from pre-RT FDG-PET may be beneficial for selecting patients who are likely to respond to EBRT for unresectable HCC.

Peripheral Blood Lymphocyte Depletion After Hepatic Arterial 90Yttrium Microsphere Therapy for Hepatocellular Carcinoma

Brian I. Carr, Diana M. Metes — 2011-05-23

Purpose: The short- and long-term effects of 90Yttrium microspheres therapy for hepatocellular carcinoma (HCC) on peripheral blood lymphocytes are unknown and were therefore examined.Methods and Materials: Ninety-two HCC patients were enrolled in a 90Yttrium therapy study and routine blood counts were examined as part of standard clinical monitoring.Results: We found an early, profound, and prolonged lymphopenia. In a subsequent cohort of 25 additional HCC patients, prospective flow cytometric immune-monitoring analysis was performed to identify specific changes on distinct lymphocyte subsets (i.e., CD3, CD4, CD8 T, and CD19 B lymphocytes) and NK cells absolute numbers, in addition to the granulocytes and platelets subsets. We found that the pretreatment lymphocyte subset absolute numbers (with the exception of NK cells) had a tendency to be lower compared with healthy control values, but no significant differences were detected between groups. Posttherapy follow-up revealed that overall, all lymphocyte subsets, except for NK cells, were significantly (>50% from pretherapy values), promptly (as early as 24 h) and persistently (up to 30 months) depleted post-90Yttrium microspheres therapy. In contrast, granulocytes increased rapidly (24 h) to compensate for lymphocyte depletion, and remained increased at 1-year after therapy. We further stratified patients into two groups, according to survival at 1 year. We found that lack of recovery of CD19, CD3, CD8, and especially CD4 T cells was linked to poor patient survival. No fungal or bacterial infections were noted during the 30-month follow-up period.Conclusions: The results show that lymphocytes (and not granulocytes, platelets, or NK cells) are sensitive to hepatic arterial 90Yttrium without associated clinical toxicity, and lack of lymphocyte recovery (possibly leading to dysregulation of adaptive cellular immunity) posttherapy indicates poor survival.

Basal Subtype of Invasive Breast Cancer Is Associated With a Higher Risk of True Recurrence After Conventional Breast-Conserving Therapy

2011-05-20

Purpose: To determine whether breast cancer subtype is associated with patterns of ipsilateral breast tumor recurrence (IBTR), either true recurrence (TR) or elsewhere local recurrence (ELR), among women with pT1–T2 invasive breast cancer (IBC) who receive breast-conserving therapy (BCT).Methods and Materials: From Jan 1998 to Dec 2003, 1,223 women with pT1–T2N0-3 IBC were treated with BCT (lumpectomy plus whole-breast radiation). Ninety percent of patients received adjuvant systemic therapy, but none received trastuzumab. Biologic cancer subtypes were approximated by determining estrogen receptor-positive (ER+), progesterone receptor-positive (PR+), and human epidermal growth factor receptor-2-positive (HER-2+) expression, classified as luminal A (ER+ or PR+ and HER-2 negative [HER-2−]), luminal B (ER+ or PR+ and HER-2+), HER-2 (ER− and PR− and HER-2+), and basal (ER− and PR− and HER-2− ) subtypes. Imaging, pathology, and operative reports were reviewed by two physicians independently, including an attending breast radiologist. Readers were blinded to subtype and outcome. TR was defined as IBTR within the same quadrant and within 3 cm of the primary tumor. All others were defined as ELR.Results: At a median follow-up of 70 months, 24 patients developed IBTR (5-year cumulative incidence of 1.6%), including 15 TR and 9 ELR patients. At 5 years, basal (4.4%) and HER-2 (9%) subtypes had a significantly higher incidence of TR than luminal B (1.2%) and luminal A (0.2%) subtypes (p < 0.0001). On multivariate analysis, basal subtype (hazard ratio [HR], 4.8, p = 0.01), younger age at diagnosis (HR, 0.97; p = 0.05), and increasing tumor size (HR, 2.1; p = 0.04) were independent predictors of TR. Only younger age (HR, 0.95; p = 0.01) significantly predicted for ELR.Conclusions: Basal and HER-2 subtypes are significantly associated with higher rates of TR among women with pT1–T2 IBC after BCT. Younger age predicts for both TR and ELR. Strategies to reduce TR in basal breast cancers, such as increased boost doses, concomitant radiation and chemotherapy, or targeted therapy agents, should be explored.

Higher Chest Wall Dose Results in Improved Locoregional Outcome in Patients Receiving Postmastectomy Radiation

2011-04-25

Purpose: Randomized trials demonstrating decreased locoregional recurrence (LRR) and improved overall survival (OS) in women receiving postmastectomy radiation therapy (PMRT) used up to 50 Gy to the chest wall (CW), but in practice, many centers boost the CW dose to ≥60 Gy, despite lack of data supporting this approach. We evaluated the relationship between CW dose and clinical outcome.Methods and Materials: We retrospectively reviewed medical records of 582 consecutively treated patients who received PMRT between January 1999 and December 2009. We collected data on patient, disease, treatment characteristics, and outcomes of LRR, progression-free survival (PFS) and OS.Results: Median follow-up from the date of diagnosis was 44.7 months. The cumulative 5-year incidence of LRR as first site of failure was 6.2%. CW dose for 7% (43 patients) was ≤50.4 Gy (range, 41.4–50.4 Gy) and 93% received >50.4 Gy (range, 52.4–74.4 Gy). A CW dose of >50.4 Gy vs. ≤50.4 Gy was associated with lower incidence of LRR, a 60-month rate of 5.7% (95% confidence interval [CI], 3.7–8.2) vs. 12.7% (95% CI, 4.5–25.3; p = 0.054). Multivariate hazard ratio (HR) for LRR controlling for race, receptor status, and stage was 2.62 (95% CI, 1.02–7.13; p = 0.042). All LRR in the low-dose group occurred in patients receiving 50 to 50.4 Gy. Lower CW dose was associated with worse PFS (multivariate HR, 2.73; 95% CI, 1.64–4.56; p < 0.001) and OS (multivariate HR, 3.88; 95% CI, 2.16–6.99; p < 0.001).Conclusions: The addition of a CW boost above 50.4 Gy resulted in improved locoregional control and survival in this cohort patients treated with PMRT for stage II–III breast cancer. The addition of a CW boost to standard-dose PMRT is likely to benefit selected high-risk patients. The optimal technique, target volume, and patient selection criteria are unknown. The use of a CW boost should be studied prospectively, as has been done in the setting of breast conservation.

Impact of Lymph Node Status on Clinical Outcomes After Accelerated Partial Breast Irradiation

2011-09-22

Purpose: To compare outcomes after accelerated partial breast irradiation (APBI) between node-negative and node-positive patients.Methods and Materials: A total of 534 patients with early-stage breast cancer received APBI including 39 node-positive (N+) cases. Clinical, pathologic, and treatment-related factors were compared between node-negative (N–) and N+ cohorts. Local recurrence (LR), regional recurrence (RR), axillary failure (AF), distant metastases (DM), disease-free survival (DFS), cause-specific survival (CSS), and overall survival (OS) were analyzed.Results: N+ patients were younger (p = 0.04), had larger tumors (p < 0.001), and were more likely to receive chemotherapy (p < 0.001). Mean follow-up was 7.8 years for N+ patients and 6.3 years for N– patients (p = 0.06). No differences were seen in 5-year actuarial rates of LR (2.2% vs. 2.6%, p = 0.86), AF (0% vs. 0%, p = 0.69), DFS (90.0% vs. 88.0%, p = 0.79), or OS (91.0 vs. 84.0%, p = 0.65) between the two groups, whereas higher rates of RR (0% vs. 6.1%, p < 0.001) and DM (2.2% vs. 8.9%, p = 0.005) were noted in N+ patients. A trend for improved CSS (p = 0.06), was seen in N– patients. Age, tumor size, receptor status, T-stage, chemotherapy, APBI technique, and nodal status (p = 0.86) were not associated with LR, while a trend for an association with LR was noted with close/positive margins, (p = 0.07), and failure to receive adjuvant hormonal therapy (p = 0.06).Conclusions: No differences were seen in the rates of LR or AF between N– and N+ patients after APBI. These results support the continued enrollment of node-positive patients in Phase III trials evaluating the efficacy of APBI including the National Surgical Adjuvant Breast and Bowel Project-B39/Radiation Therapy Oncology Group 0413.

Prone Hypofractionated Whole-Breast Radiotherapy Without a Boost to the Tumor Bed: Comparable Toxicity of IMRT Versus a 3D Conformal Technique

2011-10-21

Purpose: We report a comparison of the dosimetry and toxicity of three-dimensional conformal radiotherapy (3D-CRT) vs. intensity-modulated radiotherapy (IMRT) among patients treated in the prone position with the same fractionation and target of the hypofractionation arm of the Canadian/Whelan trial.Methods and Materials: An institutional review board–approved protocol identified a consecutive series of early-stage breast cancer patients treated according to the Canadian hypofractionation regimen but in the prone position. Patients underwent IMRT treatment planning and treatment if the insurance carrier approved reimbursement for IMRT; in case of refusal, a 3D-CRT plan was used. A comparison of the dosimetric and toxicity outcomes during the acute, subacute, and long-term follow-up of the two treatment groups is reported.Results: We included 97 consecutive patients with 100 treatment plans in this study (3 patients with bilateral breast cancer); 40 patients were treated with 3D-CRT and 57 with IMRT. IMRT significantly reduced the maximum dose (Dmax median, 109.96% for 3D-CRT vs. 107.28% for IMRT; p < 0.0001, Wilcoxon test) and improved median dose homogeneity (median, 1.15 for 3D-CRT vs. 1.05 for IMRT; p < 0.0001, Wilcoxon test) when compared with 3D-CRT. Acute toxicity consisted primarily of Grade 1 to 2 dermatitis and occurred in 92% of patients. Grade 2 dermatitis occurred in 13% of patients in the 3D-CRT group and 2% in the IMRT group. IMRT moderately decreased rates of acute pruritus (p = 0.03, chi-square test) and Grade 2 to 3 subacute hyperpigmentation (p = 0.01, Fisher exact test). With a minimum of 6 months’ follow-up, the treatment was similarly well tolerated in either group, including among women with large breast volumes.Conclusion: Hypofractionated breast radiotherapy is well tolerated when treating patients in the prone position, even among those with large breast volumes. Breast IMRT significantly improves dosimetry but yields only a modest but confirmed benefit in terms of toxicities. If a concurrent boost to the tumor bed is not required, a conformal 3D-CRT approach can adequately deliver prone whole-breast hypofractionation radiotherapy.

Validating Fiducial Markers for Image-Guided Radiation Therapy for Accelerated Partial Breast Irradiation in Early-Stage Breast Cancer

2012-03-01

Purpose: Image-guided radiation therapy (IGRT) may be beneficial for accelerated partial breast irradiation (APBI). The goal was to validate the use of intraparenchymal textured gold fiducials in patients receiving APBI.Methods and Materials: Twenty-six patients were enrolled on this prospective study that had three or four textured gold intraparenchymal fiducials placed at the periphery of the lumpectomy cavity and were treated with three-dimensional (3D) conformal APBI. Free-breathing four-dimensional computed tomography image sets were obtained pre- and posttreatment, as were daily online megavoltage (MV) orthogonal images. Intrafraction motion, variations in respiratory motion, and fiducial marker migration were calculated using the 3D coordinates of individual fiducials and a calculated center of mass (COM) of the fiducials. We also compared the relative position of the fiducial COM with the geometric center of the seroma.Results: There was less than 1 mm of intrafraction respiratory motion, variation in respiratory motion, or fiducial marker migration. The change in seroma position relative to the fiducial COM was 1 mm ± 1 mm. The average position of the geometric seroma relative to the fiducial COM pretreatment compared with posttreatment was 1 mm ± 1 mm. The largest daily variation in displacement when using bony landmark was in the anteroposterior direction and two standard deviations (SD) of this variation was 10 mm. The average variation in daily separation between the fiducial pairs from daily MV images was 3 mm ± 3 mm therefore 2 SD is 6 mm.Conclusion: Fiducial markers are stable throughout the course of APBI. Planning target volume margins when using bony landmarks should be 10 mm and can be reduced to 6 mm if using fiducials.

Later Outcomes and Alpha/Beta Estimate From Hypofractionated Conformal Three-Dimensional Radiotherapy Versus Standard Fractionation for Localized Prostate Cancer

Felix Leborgne, Jack Fowler, José H. Leborgne, Julieta Mezzera — 2011-04-07

Purpose: Now that the follow-up time has exceeded 5 years, an estimate of the α/β ratio can be presented. The additional late outcomes in patients treated with three-dimensional conformal external beam radiotherapy for localized prostate cancer using a hypofractionated vs. a standard fractionation regimen are reported from this prospective nonrandomized contemporary comparison.Methods and Materials: A total of 114 nonrandomized patients chose hypofractionation delivered in 20 fractions of 3 Gy or 3.15 Gy (mean 3.06 Gy) for localized prostate cancer within a median overall time of 32 days (range, 29–49) using four fractions weekly. A total of 160 comparable patients were contemporarily treated within a median of 55 days (range 49-66). The median follow-up was 66 months (range, 24–95) for the hypofractionated arm and 63 months (range, 36–92) for the standard arm. The percentage of patients in the low-, medium-, and high-risk groups was 36%, 46%, and 18% in the hypofractionated arm and 44%, 50%, and 6% in standard arm (2 Gy), respectively.Results: The 5-year actuarial biochemical absence of disease (prostate-specific antigen nadir + 2 ng/mL) and disease-free survival rate was the same at 89% in both arms, making the α/β calculation unambiguous. The point ratio of α/β was 1.86 (95% confidence interval, 0.7–5.1 Gy). The 95% confidence interval was determined entirely by the binomial confidence limits in the numbers of patients. Rectal reactions of grade 3 and 4 occurred in 1 of 114 (hypofractionated) and 2 of 160 (standard) patients.Conclusions: The presented three-dimensional conformal regimen was acceptable, and the α/β value was 1.8, in agreement with other very recent low meta-analyses (reviewed in the “” section).

Role of Intra- or Periprostatic Calcifications in Image-Guided Radiotherapy for Prostate Cancer

2011-06-02

Purpose: Image-guided radiotherapy (IGRT) allows more precise localization of the prostate, thus minimizing errors resulting from organ motion and set-up during treatment of prostate cancer. Using megavoltage cone-beam computed tomography (MVCBCT), references such as bones, the prostate itself or implanted fiducial markers can be used as surrogates to correct patient positioning immediately before each treatment fraction. However, the use of fiducials requires an invasive procedure and may increase costs. We aimed to assess whether intra- or periprostatic calcifications (IPC) could be used as natural fiducials.Methods and Materials: Data on patients treated with IGRT for prostate cancer with clearly visible IPC and implanted fiducials in both planning CT and MVCBCT images were reviewed. IPC were classified as central when inside the prostate and peripheral when within the planning target volume. Daily deviations in lateral, longitudinal, and vertical directions from baseline positioning using fiducials and using IPC were compared.Results: A total of 287 MVCBCT images were obtained and analyzed from 10 patients. The mean ± standard deviation daily deviation (mm) in the lateral, longitudinal, and vertical coordinates were 0.55 ± 3.11, 0.58 ± 3.45, and −0.54 ± 4.03, respectively, for fiducials, and 0.72 ± 3.22, 0.63 ± 3.58, and −0.69 ± 4.26, for IPC. The p values for comparisons (fiducials vs. IPC) were 0.003, 0.653, and 0.078 for lateral, longitudinal, and vertical coordinates, respectively. When cases with central IPC were analyzed (n = 7), no significant difference was found in such comparisons. Central IPC and fiducials exhibited a similar pattern of displacement during treatment, with equal values for daily displacements in the three directions for more than 90% of measurements.Conclusions: Our data suggest that centrally located IPC may be used as natural fiducials for treatment positioning during IGRT for prostate cancer, with potential reductions in the risks and costs associated with fiducial implantation.

Prostate-Specific Antigen Velocity Before and After Elimination of Factors That Can Confound the Prostate-Specific Antigen Level

Jessica J. Park, Ming-Hui Chen, Marian Loffredo, Anthony V. D’Amico — 2011-06-02

Purpose: Prostate-specific antigen (PSA) velocity, like PSA level, can be confounded. In this study, we estimated the impact that confounding factors could have on correctly identifying a patient with a PSA velocity >2 ng/ml/y.Methods and Materials: Between 2006 and 2010, a total of 50 men with newly diagnosed PC comprised the study cohort. We calculated and compared the false-positive and false-negative PSA velocity >2 ng/ml/y rates for all men and those with low-risk disease using two approaches to calculate PSA velocity. First, we used PSA values obtained within 18 months of diagnosis; second, we used values within 18 months of diagnosis, substituting the prebiopsy PSA for a repeat, nonconfounded PSA that was obtained using the same assay and without confounders.Results: Using PSA levels pre-biopsy, 46% of all men had a PSA velocity >2 ng/ml/y; whereas this value declined to 32% when substituting the last prebiopsy PSA for a repeat, nonconfounded PSA using the same assay and without confounders. The false-positive rate for PSA velocity >2 ng/ml/y was 43% as compared with a false-negative rate of PSA velocity >2 ng/ml/y of 11% (p = 0.0008) in the overall cohort. These respective values in the low-risk subgroup were 60% and 16.7% (p = 0.09).Conclusion: This study provides evidence to explain the discordance in cancer-specific outcomes among groups investigating the prognostic significance of PSA velocity >2 ng/ml/y, and highlights the importance of patient education on potential confounders of the PSA test before obtaining PSA levels.

Proton Radiotherapy for Prostate Cancer Is Not Associated With Post-Treatment Testosterone Suppression

2011-05-12

Purpose: Three independent studies of photon (x-ray) radiotherapy (RT) for prostate cancer have demonstrated evidence of testosterone suppression after treatment. The present study was undertaken to determine whether this would also be the case with conformal protons.Methods and Materials: Between August 2006 and October 2007, 171 patients with low- and intermediate-risk prostate cancer were enrolled and underwent treatment according to the University of Florida Proton Therapy Institute institutional review board-approved PR01 and PR02 protocols. Of the 171 patients, 18 were excluded because they had received androgen deprivation therapy either before (n = 17) or after (n = 1) RT. The pretreatment serum testosterone level was available for 150 of the remaining 153 patients. These 150 patients were included in the present study. The post-treatment levels were compared with the pretreatment levels.Results: The median baseline pretreatment serum testosterone level was 357.9 ng/dL. The median post-treatment testosterone value was 375.5 ng/dL at treatment completion (p = .1935) and 369.9 ng/dL (p = .1336), 348.7 ng/dL (p = .7317), 353.4 ng/dL (p = .6996), and 340.9 ng/dL (p = .1669) at 6, 12, 18, and 24 months after proton therapy, respectively.Conclusions: Conformal proton therapy to the prostate, as delivered using the University of Florida Proton Therapy Institute PR01 and PR02 protocols, did not appear to significantly affect the serum testosterone levels within 24 months after RT.

Concurrent Androgen Deprivation Therapy During Salvage Prostate Radiotherapy Improves Treatment Outcomes in High-Risk Patients

Daniel E. Soto, Michael N. Passarelli, Stephanie Daignault, Howard M. Sandler — 2011-05-06

Purpose: To determine whether concurrent androgen deprivation therapy (ADT) during salvage radiotherapy (RT) improves prostate cancer treatment outcomes.Methods and Materials: A total of 630 postprostatectomy patients were retrospectively identified who were treated with three-dimensional conformal RT. Of these, 441 were found to be treated for salvage indications. Biochemical failure was defined as prostate-specific antigen (PSA) of 0.2 ng/mL or greater above nadir with another PSA increase or the initiation of salvage ADT. Progression-free survival (PFS) was defined as the absence of biochemical failure, continued PSA rise despite salvage therapy, initiation of systemic therapy, clinical progression, or distant failure. Multivariate-adjusted Cox proportional hazards modeling was performed to determine which factors predict PFS.Results: Low-, intermediate-, and high-risk patients made up 10%, 24%, and 66% of patients, respectively. The mean RT dose was 68 Gy. Twenty-four percent of patients received concurrent ADT (cADT). Regional pelvic nodes were treated in 16% of patients. With a median follow-up of 3 years, the 3-year PFS was 4.0 years for cADT vs. 3.4 years for cADT patients (p = 0.22). Multivariate analysis showed that concurrent ADT (p = 0.05), Gleason score (p < 0.001), and pre-RT PSA (p = 0.03) were independent predictors of PFS. When patients were stratified by risk group, the benefits of cADT (hazard ratio, 0.65; p = 0.046) were significant only for high-risk patients.Conclusions: This retrospective study showed a PFS benefit of concurrent ADT during salvage prostate RT. This benefit was observed only in high-risk patients.

The Benefits of Including Clinical Factors in Rectal Normal Tissue Complication Probability Modeling After Radiotherapy for Prostate Cancer

2011-06-09

Purpose: To study the impact of clinical predisposing factors on rectal normal tissue complication probability modeling using the updated results of the Dutch prostate dose-escalation trial.Methods and Materials: Toxicity data of 512 patients (conformally treated to 68 Gy [n = 284] and 78 Gy [n = 228]) with complete follow-up at 3 years after radiotherapy were studied. Scored end points were rectal bleeding, high stool frequency, and fecal incontinence. Two traditional dose-based models (Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) and a logistic model were fitted using a maximum likelihood approach. Furthermore, these model fits were improved by including the most significant clinical factors. The area under the receiver operating characteristic curve (AUC) was used to compare the discriminating ability of all fits.Results: Including clinical factors significantly increased the predictive power of the models for all end points. In the optimal LKB, RS, and logistic models for rectal bleeding and fecal incontinence, the first significant (p = 0.011–0.013) clinical factor was “previous abdominal surgery.” As second significant (p = 0.012–0.016) factor, “cardiac history” was included in all three rectal bleeding fits, whereas including “diabetes” was significant (p = 0.039–0.048) in fecal incontinence modeling but only in the LKB and logistic models. High stool frequency fits only benefitted significantly (p = 0.003–0.006) from the inclusion of the baseline toxicity score. For all models rectal bleeding fits had the highest AUC (0.77) where it was 0.63 and 0.68 for high stool frequency and fecal incontinence, respectively. LKB and logistic model fits resulted in similar values for the volume parameter. The steepness parameter was somewhat higher in the logistic model, also resulting in a slightly lower D50. Anal wall DVHs were used for fecal incontinence, whereas anorectal wall dose best described the other two endpoints.Conclusions: Comparable prediction models were obtained with LKB, RS, and logistic NTCP models. Including clinical factors improved the predictive power of all models significantly.

Castration Therapy of Prostate Cancer Results in Downregulation of HIF-1α Levels

2012-03-01

Background and Purpose: Neoadjuvant androgen deprivation in combination with radiotherapy of prostate cancer is used to improve radioresponsiveness and local tumor control. Currently, the underlying mechanism is not well understood. Because hypoxia causes resistance to radiotherapy, we wanted to test whether castration affects the degree of hypoxia in prostate cancer.Methods and Materials: In 14 patients with locally advanced prostate cancer, six to 12 prostatic needle core biopsy specimens were taken prior to castration therapy. Bilateral orchidectomy was performed in 7 patients, and 7 were treated with a GnRH-agonist (leuprorelin). After castrationm two to four prostatic core biopsy specimens were taken, and the level of hypoxia-inducible factor-1α (HIF-1α) in cancer was determined by immunofluorescence.Results: Among biopsy specimens taken before castration, strong HIF-1α expression (mean intensity above 30) was shown in 5 patients, weak expression (mean intensity 10–30) in 3 patients, and background levels of HIF-1α (mean intensity 0–10) in 6 patients. Downregulation of HIF-1α expression after castration was observed in all 5 patients with strong HIF-1α precastration expression. HIF-1α expression was also reduced in 2 of 3 patients with weak HIF-1α precastration expression.Conclusions: Our data suggest that neoadjuvant castration decreases tumor cell hypoxia in prostate cancer, which may explain increased radiosensitivity after castration.

Hypoxic Prostate/Muscle Po2 Ratio Predicts for Outcome in Patients With Localized Prostate Cancer: Long-Term Results

2011-10-10

Purpose: To correlate tumor oxygenation status with long-term biochemical outcome after prostate brachytherapy.Methods and Materials: Custom-made Eppendorf Po2 microelectrodes were used to obtain Po2 measurements from the prostate (P), focused on positive biopsy locations, and normal muscle tissue (M), as a control. A total of 11,516 measurements were obtained in 57 men with localized prostate cancer immediately before prostate brachytherapy was given. The Eppendorf histograms provided the median Po2, mean Po2, and % <5 mm Hg or <10 mm Hg. Biochemical failure (BF) was defined using both the former American Society of Therapeutic Radiation Oncology (ASTRO) (three consecutive raises) and the current Phoenix (prostate-specific antigen nadir + 2 ng/mL) definitions. A Cox proportional hazards regression model evaluated the influence of hypoxia using the P/M mean Po2 ratio on BF.Results: With a median follow-up time of 8 years, 12 men had ASTRO BF and 8 had Phoenix BF. On multivariate analysis, P/M Po2 ratio <0.10 emerged as the only significant predictor of ASTRO BF (p = 0.043). Hormonal therapy (p = 0.015) and P/M Po2 ratio <0.10 (p = 0.046) emerged as the only independent predictors of the Phoenix BF. Kaplan-Meier freedom from BF for P/M ratio <0.10 vs. ≥0.10 at 8 years for ASTRO BF was 46% vs. 78% (p = 0.03) and for the Phoenix BF was 66% vs. 83% (p = 0.02).Conclusions: Hypoxia in prostate cancer (low mean P/M Po2 ratio) significantly predicts for poor long-term biochemical outcome, suggesting that novel hypoxic strategies should be investigated.

Pathological Predictors for Site of Local Recurrence After Radiotherapy for Prostate Cancer

2012-03-01

Purpose: Rational design of targeted radiotherapy (RT) in prostate cancer (Pca) hinges on a better understanding of spatial patterns of recurrence. We sought to identify pathological factors predictive for site of local recurrence (LR) after external beam RT.Methods and Materials: Prospective databases were reviewed to identify men with LR after RT from 1997 through 2009. Patients with biochemical failure and biopsy-confirmed Pca more than 2 years after RT were evaluated. Prediction for site of recurrence based on the following pretreatment factors was determined on independent and cluster-sextant basis: presence of malignancy, dominant vs. nondominant percentage core length (PCL) involvement, PCL ≥ or <40%, and Gleason score. Sites of dominant PCL were defined as sextants with peak PCL involvement minus 10%, and >5% for each patient.Results: Forty-one patients with low-intermediate risk Pca constituted the study cohort. Median time to biopsy after RT was 51 months (range, 24–145). Of 246 sextants, 74 were involved with tumor at baseline. When sextants are treated as independent observations the presence of malignancy (77% vs. 22%, p = 0.0001), dominant PCL (90% vs. 46%, p = 0.0001), and PCL ≥40% (89% vs. 68 %, p = 0.04) were found to be significant predictors for LR, although PCL ≥40% did not retain statistical significance if sextants were considered correlated. The vast majority of patients (95%) recurred at the original site of dominant PCL or PCL ≥40%, and 44% also recurred in regions of nondominant PCL <40% (n = 8) and/or benign sampling (n = 14) at baseline.Conclusions: LR after RT predominantly occurs in regions bearing higher histological tumor burden but are not isolated to these sites. Our data highlights the value of spatially resolved baseline pathological sampling and may assist in the design of clinical trials tailoring RT dose prescriptions to subregions of the prostate gland.

20 Gy Versus 44 Gy of Supplemental External Beam Radiotherapy With Palladium-103 for Patients With Greater Risk Disease: Results of a Prospective Randomized Trial

2011-12-22

Purpose: The necessity of external beam radiotherapy (EBRT) as a supplement to prostate brachytherapy remains unknown. We report brachytherapy outcomes for patients with higher risk features randomized to substantially different supplemental EBRT regimens.Methods and Materials: Between December 1999 and June 2004, 247 patients were randomized to 20 Gy vs. 44 Gy EBRT followed by a palladium-103 boost (115 Gy vs. 90 Gy). The eligibility criteria included clinically organ-confined disease with Gleason score 7–10 and/or pretreatment prostate-specific antigen (PSA) level 10–20 ng/mL. The median follow-up period was 9.0 years. Biochemical progression-free survival (bPFS) was defined as a PSA level of ≤0.40 ng/mL after nadir. The median day 0 prescribed dose covering 90% of the target volume was 125.7%; 80 men received androgen deprivation therapy (median, 4 months). Multiple parameters were evaluated for their effect on bPFS.Results: For the entire cohort, the cause-specific survival, bPFS, and overall survival rates were 97.7%, 93.2%, and 80.8% at 8 years and 96.9%, 93.2%, and 75.4% at 10 years, respectively. The bPFS rate was 93.1% and 93.4% for the 20-Gy and 44-Gy arms, respectively (p = .994). However, no statistically significant differences were found in cause-specific survival or overall survival were identified. When stratified by PSA level of ≤10 ng/mL vs. >10 ng/mL, Gleason score, or androgen deprivation therapy, no statistically significant differences in bPFS were discerned between the two EBRT regimens. On multivariate analysis, bPFS was most closely related to the preimplant PSA and clinical stage. For patients with biochemically controlled disease, the median PSA level was <0.02 ng/mL.Conclusion: The results of the present trial strongly suggest that two markedly different supplemental EBRT regimens result in equivalent cause-specific survival, bPFS, and overall survival. It is probable that the lack of benefit for a higher supplemental EBRT dose is the result of the high-quality brachytherapy dose distributions.

Whole-Pelvis or Bladder-Only Chemoradiation for Lymph Node–Negative Invasive Bladder Cancer: Single-Institution Experience

Mutahir A. Tunio, Altaf Hashmi, Abdul Qayyum, Rehan Mohsin, Ahmed Zaeem — 2011-09-23

Purpose: Whole-pelvis (WP) concurrent chemoradiation (CCRT) is the standard bladder preserving option for patients with invasive bladder cancer. The standard practice is to treat elective pelvic lymph nodes, so our aim was to evaluate whether bladder-only (BO) CCRT leads to results similar to those obtained by standard WP-CCRT.Methods and Materials: Patient eligibility included histopathologically proven muscle-invasive bladder cancer, lymph nodes negative (T2–T4, N−) by radiology, and maximal transurethral resection of bladder tumor with normal hematologic, renal, and liver functions. Between March 2005 and May 2006, 230 patients were accrued. Patients were randomly assigned to WP-CCRT (120 patients) and BO-CCRT (110 patients). Data regarding the toxicity profile, compliance, initial complete response rates at 3 months, and occurrence of locoregional or distant failure were recorded.Results: With a median follow-up time of 5 years (range, 3–6), WP-CCRT was associated with a 5-year disease-free survival of 47.1% compared with 46.9% in patients treated with BO-CCRT (p = 0.5). The bladder preservation rates were 58.9% and 57.1% in WP-CCRT and BO-CCRT, respectively (p = 0.8), and the 5-year overall survival rates were 52.9% for WP-CCRT and 51% for BO-CCRT (p = 0.8).Conclusion: BO-CCRT showed similar rates of bladder preservation, disease-free survival, and overall survival rates as those of WP-CCRT. Smaller field sizes including bladder with 2-cm margins can be used as bladder preservation protocol for patients with muscle-invasive lymph node–negative bladder cancer to minimize the side effects of CCRT.

Type of Diabetes Mellitus and the Odds of Gleason Score 8 to 10 Prostate Cancer

2011-09-22

Purpose: It has been recently shown that diabetes mellitus (DM) is significantly associated with the likelihood of presenting with high-grade prostate cancer (PCa) or Gleason score (GS) 8 to 10; however, whether this association holds for both Type 1 and 2 DM is unknown. In this study we evaluated whether DM Type 1, 2, or both are associated with high-grade PCa after adjusting for known predictors of high-grade disease.Methods and Materials: Between 1991 and 2010, a total of 15,330 men diagnosed with PCa and treated with radiation therapy were analyzed. A polychotomous logistic regression analysis was performed to evaluate whether Type 1 or 2 DM was associated with odds of GS 7 or GS 8 to 10 compared with 6 or lower PCa, adjusting for African American race, age, prostate-specific antigen (PSA) level, and digital rectal examination findings.Results: Men with Type 1 DM (adjusted odds ratio [AOR], 2.05; 95% confidence interval [CI], 1.28–3.27; p = 0.003) or Type 2 DM (AOR, 1.58; 95% CI, 1.26–1.99; p < 0.001) were significantly more likely to be diagnosed with GS 8 to 10 PCa compared with nondiabetic men. However this was not true for GS 7, for which these respective results were AOR, 1.30; 95% CI, 0.93–1.82; p = 0.12 and AOR, 1.13; 95% CI, 0.98–1.32; p = 0.10.Conclusion: Type 1 and 2 DM were associated with a higher odds of being diagnosed with Gleason score 8 to 10 but not 7 PCa. Pending validation, men who are diagnosed with Type I DM with GS 7 or lower should be considered for additional workup to rule out occult high-grade disease.

External-Beam Radiation Therapy and High–Dose Rate Brachytherapy Combined With Long-Term Androgen Deprivation Therapy in High and Very High Prostate Cancer: Preliminary Data on Clinical Outcome

2012-03-01

Purpose: To determine the feasibility of combined long-term androgen deprivation therapy (ADT) and dose escalation with high-dose-rate (HDR) brachytherapy.Methods and Materials: Between 2001 and 2007, 200 patients with high-risk prostate cancer (32.5%) or very high-risk prostate cancer (67.5%) were prospectively enrolled in this Phase II trial. Tumor characteristics included a median pretreatment prostate-specific antigen of 15.2 ng/mL, a clinical stage of T2c, and a Gleason score of 7. Treatment consisted of 54 Gy of external irradiation (three-dimensional conformal radiotherapy [3DCRT]) followed by 19 Gy of HDR brachytherapy in four twice-daily treatments. ADT started 0–3 months before 3DCRT and continued for 2 years.Results: One hundred and ninety patients (95%) received 2 years of ADT. After a median follow-up of 3.7 years (range, 2–9), late Grade ≥2 urinary toxicity was observed in 18% of the patients and Grade ≥3 was observed in 5%. Prior transurethral resection of the prostate (p = 0.013) and bladder D50 ≥1.19 Gy (p = 0.014) were associated with increased Grade ≥2 urinary complications; age ≥70 (p = 0.05) was associated with Grade ≥3 urinary complications. Late Grade ≥2 gastrointestinal toxicity was observed in 9% of the patients and Grade ≥3 in 1.5%. CTV size ≥35.8 cc (p = 0.007) and D100 ≥3.05 Gy (p = 0.01) were significant for increased Grade ≥2 complications. The 5-year and 9-year biochemical relapse-free survival (nadir + 2) rates were 85.1% and 75.7%, respectively. Patients with Gleason score of 7–10 had a decreased biochemical relapse-free survival (p = 0.007).Conclusions: Intermediate-term results at the 5-year time point indicate a favorable outcome without an increase in the rate of late complications.

External Pelvic and Vaginal Irradiation Versus Vaginal Irradiation Alone as Postoperative Therapy in Medium-Risk Endometrial Carcinoma—A Prospective Randomized Study

2011-06-14

Purpose: To evaluate the value of adjuvant external beam pelvic radiotherapy as adjunct to vaginal brachytherapy (VBT) in medium-risk endometrial carcinoma, with regard to locoregional tumor control, recurrences, survival, and toxicity.Methods and Materials: Consecutive series of 527 evaluable patients were included in this randomized trial. Median follow-up for patients alive was 62 months. The primary study endpoints were locoregional recurrences and overall survival. Secondary endpoints were recurrence-free survival, recurrence-free interval, cancer-specific survival, and toxicity.Results: Five-year locoregional relapse rates were 1.5% after external beam radiotherapy (EBRT) plus VBT and 5% after vaginal irradiation alone (p = 0.013), and 5-year overall survival rates were 89% and 90%, respectively (p = 0.548). Endometrial cancer-related death rates were 3.8% after EBRT plus VBT and 6.8% after VBT (p = 0.118). Pelvic recurrences (exclusively vaginal recurrence) were reduced by 93% by the addition of EBRT to VBT. Deep myometrial infiltration was a significant prognostic factor in this medium-risk group of endometrioid carcinomas but not International Federation of Gynecology and Obstetrics grade or DNA ploidy. Combined radiotherapy was well tolerated, with serious (Grade 3) late side effects of less than 2%. However, there was a significant difference in favor of VBT alone.Conclusions: Despite a significant locoregional control benefit with combined radiotherapy, no survival improvement was recorded, but increased late toxicity was noted in the intestine, bladder, and vagina. Combined RT should probably be reserved for high-risk cases with two or more high-risk factors. VBT alone should be the adjuvant treatment option for purely medium-risk cases.

Continuous 7-Days-A-Week External Beam Irradiation in Locally Advanced Cervical Cancer: Final Results of the Phase I/II Study

Krystyna Serkies, Rafał Dziadziuszko, Jacek Jassem — 2011-05-12

Purpose: To evaluate the feasibility and efficacy of definitive continuous 7-days-a-week pelvic irradiation without breaks between external beam radiotherapy and brachytherapy in locally advanced cervical cancer.Methods and Materials: Between November 1998 and December 1999, 30 patients with International Federation of Obstetrics and Gynecology Stage IIB or IIIB cervical cancer were included in a prospective Phase I/II study of continuous 7-days-a-week pelvic irradiation, to the total Manchester point B dose of 40.0–57.6 Gy. The first 13 patients (Group A) were given a daily tumor dose of 1.6 Gy, and the remaining 17 patients (Group B) were given 1.8 Gy. One or two immediate brachytherapy applications (point A dose 10–20 Gy, each) were performed in 28 cases.Results: Two patients did not complete the irradiation because of apparent early progression of disease during the irradiation. Eleven of the 28 evaluable patients (39%; 45% and 35% in Groups A and B, respectively) completed their treatment within the prescribed overall treatment time. Acute toxicity (including severe European Organisation for Research and Treatment of Cancer/Radiation Therapy Oncology Group Grade 3 and 4 effects in 40%) was experienced by 83% of patients and resulted in unplanned treatment interruptions in 40% of all patients (31% and 47% of patients in Groups A and B, respectively). Severe intestinal side effects occurred in 31% and 41% of Patients in Groups A and B, respectively (p = 0.71). The 5-year overall survival probability was 33%. Cancer recurrence occurred in 63% of patients: 20% inside and 57% outside the pelvis. Cumulative incidence of late severe bowel and urinary bladder toxicity at 24 months was 15%.Conclusion: Continuous irradiation in locally advanced cervical cancer is associated with a high incidence of severe acute toxicity, resulting in unplanned treatment interruptions. Late severe effects and survival after continuous radiotherapy do not substantially differ from those obtained with conventionally fractionated radiotherapy.

Dosimetric Comparison of Combined Intensity-Modulated Radiotherapy (IMRT) and Proton Therapy Versus IMRT Alone for Pelvic and Para-Aortic Radiotherapy in Gynecologic Malignancies

Abigail Berman Milby, Stefan Both, Mark Ingram, Lilie L. Lin — 2011-12-16

Purpose: To perform a dosimetric comparison of intensity-modulated radiotherapy (IMRT), passive scattering proton therapy (PSPT), and intensity-modulated proton therapy (IMPT) to the para-aortic (PA) nodal region in women with locally advanced gynecologic malignancies.Methods and Materials: The CT treatment planning scans of 10 consecutive patients treated with IMRT to the pelvis and PA nodes were identified. The clinical target volume was defined by the primary tumor for patients with cervical cancer and by the vagina and paravaginal tissues for patients with endometrial cancer, in addition to the regional lymph nodes. The IMRT, PSPT, and IMPT plans were generated using the Eclipse Treatment Planning System and were analyzed for various dosimetric endpoints. Two groups of treatment plans including proton radiotherapy were created: IMRT to pelvic nodes with PSPT to PA nodes (PSPT/IMRT), and IMRT to pelvic nodes with IMPT to PA nodes (IMPT/IMRT). The IMRT and proton RT plans were optimized to deliver 50.4 Gy or Gy (relative biologic effectiveness [RBE)), respectively. Dose–volume histograms were analyzed for all of the organs at risk. The paired t test was used for all statistical comparison.Results: The small-bowel V20, V30, V35, andV40 were reduced in PSPT/IMRT by 11%, 18%, 27%, and 43%, respectively (p < 0.01). Treatment with IMPT/IMRT demonstrated a 32% decrease in the small-bowel V20. Treatment with PSPT/IMRT showed statistically significant reductions in the body V5–20; IMPT/IMRT showed reductions in the body V5–15. The dose received by half of both kidneys was reduced by PSPT/IMRT and by IMPT/IMRT. All plans maintained excellent coverage of the planning target volume.Conclusions: Compared with IMRT alone, PSPT/IMRT and IMPT/IMRT had a statistically significant decrease in dose to the small and large bowel and kidneys, while maintaining excellent planning target volume coverage. Further studies should be done to correlate the clinical significance of these findings.

Dynamic Contrast-Enhanced MRI of Cervical Cancers: Temporal Percentile Screening of Contrast Enhancement Identifies Parameters for Prediction of Chemoradioresistance

2011-10-18

Purpose: To systematically screen the tumor contrast enhancement of locally advanced cervical cancers to assess the prognostic value of two descriptive parameters derived from dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI).Methods and Materials: This study included a prospectively collected cohort of 81 patients who underwent DCE-MRI with gadopentetate dimeglumine before chemoradiotherapy. The following descriptive DCE-MRI parameters were extracted voxel by voxel and presented as histograms for each time point in the dynamic series: normalized relative signal increase (nRSI) and normalized area under the curve (nAUC). The first to 100th percentiles of the histograms were included in a log-rank survival test, resulting in p value and relative risk maps of all percentile–time intervals for each DCE-MRI parameter. The maps were used to evaluate the robustness of the individual percentile–time pairs and to construct prognostic parameters. Clinical endpoints were locoregional control and progression-free survival. The study was approved by the institutional ethics committee.Results: The p value maps of nRSI and nAUC showed a large continuous region of percentile–time pairs that were significantly associated with locoregional control (p < 0.05). These parameters had prognostic impact independent of tumor stage, volume, and lymph node status on multivariate analysis. Only a small percentile–time interval of nRSI was associated with progression-free survival.Conclusions: The percentile–time screening identified DCE-MRI parameters that predict long-term locoregional control after chemoradiotherapy of cervical cancer.

Tumor Shrinkage Assessed by Volumetric MRI in Long-Term Follow-Up After Fractionated Stereotactic Radiotherapy of Nonfunctioning Pituitary Adenoma

2011-04-29

Purpose: To evaluate tumor control and side effects associated with fractionated stereotactic radiotherapy (FSRT) in the management of residual or recurrent nonfunctioning pituitary adenomas (NFPAs).Methods and Materials: We assessed exact tumor volume shrinkage in 16 patients with NFPA after FSRT. All patients had previously undergone surgery. Gross tumor volume (GTV) was outlined on contrast-enhanced magnetic resonance imaging (MRI) before and median 63 months (range, 28–100 months) after FSRT. MRI was performed as an axial three-dimensional gradient echo T1-weighted sequence at 1.6-mm slice thickness without gap (3D MRI).Results: Mean tumor size of all 16 pituitary adenomas before treatment was 7.4 mL (3.3–18.9 mL). We found shrinkage of the treated pituitary adenoma in all patients. Within a median follow-up of 63 months (28–100 months) an absolute mean volume reduction of 3.8 mL (0.9–12.4 mL) was seen. The mean relative size reduction compared with the volume before radiotherapy was 51% (22%–95%). Shrinkage measured by 3D MRI was greater at longer time intervals after radiotherapy. A strong negative correlation between the initial tumor volume and the absolute volume reduction after FSRT was found. There was no correlation between tumor size reduction and patient age, sex, or number of previous surgeries.Conclusions: By using 3D MRI in all patients undergoing FSRT of an NFPA, tumor shrinkage is detected. Our data demonstrate that volumetric assessment based on 3D MRI adds additional information to routinely used radiological response measurements. After FSRT a mean relative size reduction of 51% can be expected within 5 years.

Standard-Fractionated Radiotherapy for Optic Nerve Sheath Meningioma: Visual Outcome Is Predicted by Mean Eye Dose

2011-06-02

Purpose: Radiotherapy has shown its efficacy in controlling optic nerve sheath meningiomas (ONSM) tumor growth while allowing visual acuity to improve or stabilize. However, radiation-induced toxicity may ultimately jeopardize the functional benefit. The purpose of this study was to identify predictive factors of poor visual outcome in patients receiving radiotherapy for ONSM.Methods and Materials: We conducted an extensive analysis of 10 patients with ONSM with regard to clinical, radiologic, and dosimetric aspects. All patients were treated with conformal radiotherapy and subsequently underwent biannual neuroophthalmologic and imaging assessments. Pretreatment and posttreatment values of visual acuity and visual field were compared with Wilcoxon’s signed rank test.Results: Visual acuity values significantly improved after radiotherapy. After a median follow-up time of 51 months, 6 patients had improved visual acuity, 4 patients had improved visual field, 1 patient was in stable condition, and 1 patient had deteriorated visual acuity and visual field. Tumor control rate was 100% at magnetic resonance imaging assessment. Visual acuity deterioration after radiotherapy was related to radiation-induced retinopathy in 2 patients and radiation-induced mature cataract in 1 patient. Study of radiotherapy parameters showed that the mean eye dose was significantly higher in those 3 patients who had deteriorated vision.Conclusions: Our study confirms that radiotherapy is efficient in treating ONSM. Long-term visual outcome may be compromised by radiation-induced side effects. Mean eye dose has to be considered as a limiting constraint in treatment planning.

Volumetric Modulated Arc–Based Hypofractionated Stereotactic Radiotherapy for the Treatment of Selected Intracranial Arteriovenous Malformations: Dosimetric Report and Early Clinical Experience

2011-04-13

Purpose: To evaluate, with a dosimetric and clinical feasibility study, RapidArc (a volumetric modulated arc technique) for hypofractionated stereotactic radiotherapy treatment of large arteriovenous malformations (AVMs).Methods and Materials: Nine patients were subject to multimodality imaging (magnetic resonance, computed tomography, and digital subtraction angiography) to determine nidus and target volumes, as well as involved organs at risk (optical structures, inner ear, brain stem). Plans for multiple intensity-modulated arcs with a single isocenter were optimized for a fractionation of 25 Gy in 5 fractions. All plans were optimized for 6-MV photon beams. Dose–volume histograms were analyzed to assess plan quality. Delivery parameters were reported to appraise technical features of RapidArc, and pretreatment quality assurance measurements were carried out to report on quality of delivery.Results: Average size of AVM nidus was 26.2 cm3, and RapidArc plans provided complete target coverage with minimal overdosage (V100% = 100% and V110% < 1%) and excellent homogeneity (<6%). Organs at risk were highly spared. The D1% to chiasm, eyes, lenses, optic nerves, and brainstem (mean ± SD) was 6.4 ± 8.3, 1.9 ± 3.8, 2.3 ± 2.2, 0.7 ± 0.9, 4.4 ± 7.2, 12.2 ± 9.6 Gy, respectively. Conformity index (CI95%) was 2.2 ± 0.1. The number of monitor units per gray was 277 ± 45, total beam-on time was 2.5 ± 0.3 min. Planning vs. delivery γ pass rate was 98.3% ± 0.9%. None of the patients developed acute toxicity. With a median follow-up of 9 months, 3 patients presented with deterioration of symptoms and were found to have postradiation changes but responded symptomatically to steroids. These patients continue to do well on follow-up. One patient developed headache and seizures, which was attributed to intracranial bleed, confirmed on imaging.Conclusion: Hypofractionated stereotactic radiotherapy can be successfully delivered using the RapidArc form of volumetric arc technology for intracranial AVMs. The quality of delivery and calculated parameters are in agreement with each other and are in line with published reports for other sites.

Protracted Hypofractionated Radiotherapy for Graves' Ophthalmopathy: A Pilot Study of Clinical and Radiologic Response

2011-05-09

Purpose: To evaluate the clinical and radiologic response of patients with Graves’ ophthalmopathy given low-dose orbital radiotherapy (RT) with a protracted fractionation.Methods and Materials: Eighteen patients (36 orbits) received orbital RT with a total dose of 10 Gy, fractionated in 1 Gy once a week over 10 weeks. Of these, 9 patients received steroid therapy as well. Patients were evaluated clinically and radiologically at 6 months after treatment. Clinical response assessment was carried out using three criteria: by physical examination, by a modified clinical activity score, and by a verbal questionnaire considering the 10 most common signs and symptoms of the disease. Radiologic response was assessed by magnetic resonance imaging.Results: Improvement in ocular pain, palpebral edema, visual acuity, and ocular motility was observed in all patients. Significant decrease in symptoms such as tearing (p < 0.001) diplopia (p = 0.008), conjunctival hyperemia (p = 0.002), and ocular grittiness (p = 0.031) also occurred. Magnetic resonance imaging showed decrease in ocular muscle thickness and in the intensity of the T2 sequence signal in the majority of patients. Treatments were well tolerated, and to date no complications from treatment have been observed. There was no statistical difference in clinical and radiologic response between patients receiving RT alone and those receiving RT plus steroid therapy.Conclusion: RT delivered in at a low dose and in a protracted scheme should be considered as a useful therapeutic option for patients with Graves’ ophthalmopathy.

7-Tesla Susceptibility-Weighted Imaging to Assess the Effects of Radiotherapy on Normal-Appearing Brain in Patients With Glioma

2011-10-13

Purpose: To evaluate the intermediate- and long-term imaging manifestations of radiotherapy on normal-appearing brain tissue in patients with treated gliomas using 7T susceptibility-weighted imaging (SWI).Methods and Materials: SWI was performed on 25 patients with stable gliomas on a 7 Tesla magnet. Microbleeds were identified as discrete foci of susceptibility that did not correspond to vessels. The number of microbleeds was counted within and outside of the T2-hyperintense lesion. For 3 patients, radiation dosimetry maps were reconstructed and fused with the 7T SWI data.Results: Multiple foci of susceptibility consistent with microhemorrhages were observed in patients 2 years after chemoradiation. These lesions were not present in patients who were not irradiated. The prevalence of microhemorrhages increased with the time since completion of radiotherapy, and these lesions often extended outside the boundaries of the initial high-dose volume and into the contralateral hemisphere.Conclusions: High-field SWI has potential for visualizing the appearance of microbleeds associated with long-term effects of radiotherapy on brain tissue. The ability to visualize these lesions in normal-appearing brain tissue may be important in further understanding the utility of this treatment in patients with longer survival.

Dosimetric Study of Current Treatment Options for Radiotherapy in Retinoblastoma

Eman Eldebawy, William Parker, Wamied Abdel Rahman, Carolyn R. Freeman — 2011-12-23

Purpose: To determine the best treatment technique for patients with retinoblastoma requiring radiotherapy to the whole eye.Methods and Materials: Treatment plans for 3 patients with retinoblastoma were developed using 10 radiotherapy techniques including electron beams, photon beam wedge pair (WP), photon beam three-dimensional conformal radiotherapy (3D-CRT), fixed gantry intensity-modulated radiotherapy (IMRT), photon volumetric arc therapy (VMAT), fractionated stereotactic radiotherapy, and helical tomotherapy (HT). Dose-volume analyses were carried out for each technique.Results: All techniques provided similar target coverage; conformity was highest for VMAT, nine-field (9F) IMRT, and HT (conformity index [CI] = 1.3) and lowest for the WP and two electron techniques (CI = 1.8). The electron techniques had the highest planning target volume dose gradient (131% of maximum dose received [Dmax]), and the CRT techniques had the lowest (103% Dmax) gradient. The volume receiving at least 20 Gy (V20Gy) for the ipsilateral bony orbit was lowest for the VMAT and HT techniques (56%) and highest for the CRT techniques (90%). Generally, the electron beam techniques were superior in terms of brain sparing and delivered approximately one-third of the integral dose of the photon techniques.Conclusions: Inverse planned image-guided radiotherapy delivered using HT or VMAT gives better conformity index, improved orbital bone and brain sparing, and a lower integral dose than other techniques.

Conjunctival Autograft Alone or Combined With Adjuvant Beta-Radiation? A Randomized Clinical Trial

2012-03-01

Purpose: To evaluate the effectiveness and safety of postoperative low single-dose of beta-irradiation (β-RT) in pterygium comparing conjunctival autograft (CAG) surgery with CAG plus adjuvant β-RT in a randomized clinical trial.Methods: This trial was designed as a prospective, randomized, single-center study. Surgery was performed in all cases according to the CAG technique. One hundred and eight pterygia were postoperatively randomized to CAG + β-RT or CAG alone. In the case of β-RT, a (90) Sr eye applicator was used to deliver 10 Gy to the sclera surface at a dose rate of between 200 and 250 cGy/min. After treatment, both an ophthalmologist and a radiation oncologist performed the follow-up examinations. The accumulated data were analyzed using a group sequential test.Results: Between February 2008 and September 2008, 116 eyes with primary pterygium were operated on according to the trial protocol. Adjuvant treatment was performed within 24 h postoperatively. Eight patients were lost to follow-up, resulting in 108 patients who could be analyzed. At a mean follow-up of 18 months (range, 8–33), in the 54 eyes randomized to receive CAG + β-RT, 5 relapses occurred compared with 12 recurrences in the 54 eyes in CAG, for a crude control rate of 90.8 % vs. 78%; p = 0.032, respectively. The treatment complications as hyperemia, total dehiscence of the autograft and dellen were significantly more frequent in the CAG (p < 0.05). The arm of β-RT resulted in better cosmetic results and improves of symptoms than CAG.Conclusions: A low single-dose of β-RT of 10 Gy after CAG surgery was a simple, effective, and safe treatment that reduced the risk of primary pterygium recurrence, improved symptoms after surgery, resulting in a better cosmetic effect than only CAG.

Anastomotic Complications After Ivor Lewis Esophagectomy in Patients Treated With Neoadjuvant Chemoradiation Are Related to Radiation Dose to the Gastric Fundus

2011-10-18

Purpose: Neoadjuvant chemoradiation (CRT) is increasingly used in locally advanced esophageal cancer. Some studies have suggested that CRT results in increased surgical morbidity. We assessed the influence of CRT on anastomotic complications in a cohort of patients who underwent CRT followed by Ivor Lewis esophagectomy.Patients and Methods: Clinical and pathologic data were collected from all patients treated with neoadjuvant CRT (36 Gy combined with 5-fluorouracil and cisplatin) followed by Ivor Lewis esophagectomy. On the radiotherapy (RT) planning computed tomography scans, normal tissue volumes were drawn encompassing the proximal esophageal region and the gastric fundus. Within these volumes, dose–volume histograms were analyzed to generate the total dose to 50% of the volume (D50). We studied the ability of the D50 to predict anastomotic complications (leakage, ischemia, or stenosis). Dose limits were derived using receiver operating characteristics analysis.Results: Fifty-four patients were available for analysis. RT resulted in either T or N downstaging in 51% of patients; complete pathologic response was achieved in 11%. In-hospital mortality was 5.4%, and major morbidity occurred in 36% of patients. Anastomotic complications (AC) developed in 7 patients (13%). No significant influence of the D50 on the proximal esophagus was noted on the anastomotic complication rate. The median D50 on the gastric fundus, however, was 33 Gy in patients with AC and 18 Gy in patients without AC (p = 0.024). Using receiver operating characteristics analysis, the D50 limit on the gastric fundus was defined as 29 Gy.Conclusions: In patients undergoing neoadjuvant CRT followed by Ivor Lewis esophagectomy, the incidence of AC is related to the RT dose on the gastric fundus but not to the dose received by the proximal esophagus. When planning preoperative RT, efforts should be made to limit the median dose on the gastric fundus to 29 Gy with a V30 below 40%.

Regional Differences in Stem and Transit Cell Proliferation and Apoptosis in the Terminal Ileum and Colon of Mice After 12 Gy

Ricardo M.C. Gândara, Yashwant R. Mahida, Christopher S. Potten — 2011-12-22

Purpose: The intestinal epithelium has a high rate of cell turnover, which is regulated by stem cells located near the base of crypts. We aimed to investigate stem cell–dependent characteristics of cell proliferation, apoptosis, and crypt size in terminal ileum and different regions of the colon.Methods and Materials: Mice were studied under steady-state conditions and after radiation-induced stem cell apoptosis. Percentage of proliferating or apoptotic cells at a particular cell position (cp) along the crypt axis was expressed as labeling or apoptotic index.Results: Under steady-state conditions: crypt size was smallest in the ascending colon. In contrast to other regions of the colon, the distribution profile of proliferating cells in ascending colon showed some similarity to that in the terminal ileum. Postirradiation: apoptotic cells were prominent at the bottom of the crypt of mid- and descending colon but in the ascending colon, they were seen with similar frequency from cp 1 to 4. During regeneration, a constant proliferative capacity was seen above Paneth cells in the terminal ileum. In the ascending (but not mid- or descending) colon, the profile of proliferating cells over the first 4 days after irradiation showed a similarity to that in the terminal ileum.Conclusions: Profiles of proliferating epithelial cells (under steady-state conditions and postirradiation) and apoptotic cells (postirradiation) suggest similarities in the location of stem cells in the ascending colon and terminal ileum.

Evaluation of Liver Function After Proton Beam Therapy for Hepatocellular Carcinoma

2012-03-01

Purpose: Our previous results for treatment of hepatocellular carcinoma with proton beam therapy (PBT) revealed excellent local control. In this study, we focused on the impact of PBT on normal liver function.Methods and Materials: The subjects were 259 patients treated with PBT at the University of Tsukuba between January 2001 and December 2007. We evaluated the Child–Pugh score pretreatment, on the final day of PBT, and 6, 12, and 24 months after treatment with PBT. Patients who had disease progression or who died with tumor progression at each evaluation point were excluded from the analysis to rule out an effect of tumor progression. An increase in the Child–Pugh score of 1 or more was defined as an adverse event.Results: Of the 259 patients, 241 had no disease progression on the final day of PBT, and 91 had no progression within 12 months after PBT. In univariate analysis, the percentage volumes of normal liver receiving at least 0, 10, 20, and 30 GyE in PBT (V0, 10, 20, and 30) were significantly associated with an increase of Child–Pugh score at 12 months after PBT. Of the 91 patients evaluated at 12 months, 66 had no increase of Child–Pugh score, 15 had a 1-point increase, and 10 had an increase of ≥2 points. For the Youden index, the optimal cut-offs for V0, V10, V20, and V30 were 30%, 20%, 26%, and 18%, respectively.Conclusion: Our findings indicate that liver function after PBT is significantly related to the percentage volume of normal liver that is not irradiated. This suggests that further study of the relationship between liver function and PBT is required.

Biological Optimization in Volumetric Modulated Arc Radiotherapy for Prostate Carcinoma

2011-05-12

Purpose: To investigate the potential benefits achievable with biological optimization for modulated volumetric arc (VMAT) treatments of prostate carcinoma.Methods and Materials: Fifteen prostate patient plans were studied retrospectively. For each case, planning target volume, rectum, and bladder were considered. Three optimization schemes were used: dose–volume histogram (DVH) based, generalized equivalent uniform dose (gEUD) based, and mixed DVH/gEUD based. For each scheme, a single or dual 6-MV, 356° VMAT arc was used. The plans were optimized with Pinnacle3 (v. 9.0 beta) treatment planning system. For each patient, the optimized dose distributions were normalized to deliver the same prescription dose. The quality of the plans was evaluated by dose indices (DIs) and gEUDs for rectum and bladder. The tallied DIs were D1%, D15%, D25%, and D40%, and the tallied gEUDs were for a values of 1 and 6. Statistical tests were used to quantify the magnitude and the significance of the observed differences. Monitor units and treatment times for each optimization scheme were also assessed.Results: All optimization schemes generated clinically acceptable plans. The statistical tests indicated that biological optimization yielded increased organs-at-risk sparing, ranging from ∼1% to more than ∼27% depending on the tallied DI, gEUD, and anatomical structure. The increased sparing was at the expense of longer treatment times and increased number of monitor units.Conclusions: Biological optimization can significantly increase the organs-at-risk sparing in VMAT optimization for prostate carcinoma. In some particular cases, however, the DVH-based optimization resulted in superior treatment plans.

Pathologic Validation of a Model Based on Diffusion-Weighted Imaging and Dynamic Contrast-Enhanced Magnetic Resonance Imaging for Tumor Delineation in the Prostate Peripheral Zone

2011-12-26

Purpose: For focal boost strategies in the prostate, the robustness of magnetic resonance imaging—based tumor delineations needs to be improved. To this end we developed a statistical model that predicts tumor presence on a voxel level (2.5×2.5×2.5 mm3) inside the peripheral zone. Furthermore, we show how this model can be used to derive a valuable input for radiotherapy treatment planning.Methods and Materials: The model was created on 87 radiotherapy patients. For the validation of the voxelwise performance of the model, an independent group of 12 prostatectomy patients was used. After model validation, the model was stratified to create three different risk levels for tumor presence: gross tumor volume (GTV), high-risk clinical target volume (CTV), and low-risk CTV.Results: The model gave an area under the receiver operating characteristic curve of 0.70 for the prediction of tumor presence in the prostatectomy group. When the registration error between magnetic resonance images and pathologic delineation was taken into account, the area under the curve further improved to 0.89. We propose that model outcome values with a high positive predictive value can be used to define the GTV. Model outcome values with a high negative predictive value can be used to define low-risk CTV regions. The intermediate outcome values can be used to define a high-risk CTV.Conclusions: We developed a logistic regression with a high diagnostic performance for voxelwise prediction of tumor presence. The model output can be used to define different risk levels for tumor presence, which in turn could serve as an input for dose planning. In this way the robustness of tumor delineations for focal boost therapy can be greatly improved.

Electromagnetic Detection and Real-Time DMLC Adaptation to Target Rotation During Radiotherapy

2011-10-18

Purpose: Intrafraction rotation of more than 45° and 25° has been observed for lung and prostate tumors, respectively. Such rotation is not routinely adapted to during current radiotherapy, which may compromise tumor dose coverage. The aim of the study was to investigate the geometric and dosimetric performance of an electromagnetically guided real-time dynamic multileaf collimator (DMLC) tracking system to adapt to intrafractional tumor rotation.Materials/Methods: Target rotation was provided by changing the treatment couch angle. The target rotation was measured by a research Calypso system integrated with a real-time DMLC tracking system employed on a Varian linac. The geometric beam-target rotational alignment difference was measured using electronic portal images. The dosimetric accuracy was quantified using a two-dimensional ion chamber array. For each beam, the following five delivery modes were tested: 1) nonrotated target (reference); 2) fixed rotated target with tracking; 3) fixed rotated target without tracking; 4) actively rotating target with tracking; and 5) actively rotating target without tracking. Dosimetric performance of the latter four modes was measured and compared to the reference dose distribution using a 3 mm/3% γ-test.Results: Geometrically, the beam-target rotational alignment difference was 0.3° ± 0.6° for fixed rotation and 0.3° ± 1.3° for active rotation. Dosimetrically, the average failure rate for the γ-test for a fixed rotated target was 11% with tracking and 36% without tracking. The average failure rate for an actively rotating target was 9% with tracking and 35% without tracking.Conclusions: For the first time, real-time target rotation has been accurately detected and adapted to during radiation delivery via DMLC tracking. The beam-target rotational alignment difference was mostly within 1°. Dose distributions to fixed and actively rotating targets with DMLC tracking were significantly superior to those without tracking.

Spine Stereotactic Body Radiotherapy Utilizing Cone-Beam CT Image-Guidance With a Robotic Couch: Intrafraction Motion Analysis Accounting for all Six Degrees of Freedom

2012-03-01

Purpose: To evaluate the residual setup error and intrafraction motion following kilovoltage cone-beam CT (CBCT) image guidance, for immobilized spine stereotactic body radiotherapy (SBRT) patients, with positioning corrected for in all six degrees of freedom.Methods and Materials: Analysis is based on 42 consecutive patients (48 thoracic and/or lumbar metastases) treated with a total of 106 fractions and 307 image registrations. Following initial setup, a CBCT was acquired for patient alignment and a pretreatment CBCT taken to verify shifts and determine the residual setup error, followed by a midtreatment and posttreatment CBCT image. For 13 single-fraction SBRT patients, two midtreatment CBCT images were obtained. Initially, a 1.5-mm and 1° tolerance was used to reposition the patient following couch shifts which was subsequently reduced to 1 mm and 1° degree after the first 10 patients.Results: Small positioning errors after the initial CBCT setup were observed, with 90% occurring within 1 mm and 97% within 1°. In analyzing the impact of the time interval for verification imaging (10 ± 3 min) and subsequent image acquisitions (17 ± 4 min), the residual setup error was not significantly different (p > 0.05). A significant difference (p = 0.04) in the average three-dimensional intrafraction positional deviations favoring a more strict tolerance in translation (1 mm vs. 1.5 mm) was observed. The absolute intrafraction motion averaged over all patients and all directions along x, y, and z axis (± SD) were 0.7 ± 0.5 mm and 0.5 ± 0.4 mm for the 1.5 mm and 1 mm tolerance, respectively. Based on a 1-mm and 1° correction threshold, the target was localized to within 1.2 mm and 0.9° with 95% confidence.Conclusion: Near-rigid body immobilization, intrafraction CBCT imaging approximately every 15–20 min, and strict repositioning thresholds in six degrees of freedom yields minimal intrafraction motion allowing for safe spine SBRT delivery.

Role of Insulin-Like Growth Factor-1 Signaling Pathway in Cisplatin-Resistant Lung Cancer Cells

2011-12-23

Purpose: The development of drug-resistant phenotypes has been a major obstacle to cisplatin use in non–small-cell lung cancer. We aimed to identify some of the molecular mechanisms that underlie cisplatin resistance using microarray expression analysis.Methods and Materials: H460 cells were treated with cisplatin. The differences between cisplatin-resistant lung cancer cells and parental H460 cells were studied using Western blot, MTS, and clonogenic assays, in vivo tumor implantation, and microarray analysis. The cisplatin-R cells were treated with human recombinant insulin-like growth factor (IGF) binding protein-3 and siRNA targeting IGF-1 receptor.Results: Cisplatin-R cells illustrated greater expression of the markers CD133 and aldehyde dehydrogenase, more rapid in vivo tumor growth, more resistance to cisplatin- and etoposide-induced apoptosis, and greater survival after treatment with cisplatin or radiation than the parental H460 cells. Also, cisplatin-R demonstrated decreased expression of insulin-like growth factor binding protein-3 and increased activation of IGF-1 receptor signaling compared with parental H460 cells in the presence of IGF-1. Human recombinant IGF binding protein-3 reversed cisplatin resistance in cisplatin-R cells and targeting of IGF-1 receptor using siRNA resulted in sensitization of cisplatin-R-cells to cisplatin and radiation.Conclusions: The IGF-1 signaling pathway contributes to cisplatin-R to cisplatin and radiation. Thus, this pathway represents a potential target for improved lung cancer response to treatment.

Development and Impact Evaluation of an E-Learning Radiation Oncology Module

2011-10-24

Purpose: Radiation oncologists are faced with the challenge of irradiating tumors to a curative dose while limiting toxicity to healthy surrounding tissues. This can be achieved only with superior knowledge of radiologic anatomy and treatment planning. Educational resources designed to meet these specific needs are lacking. A web-based interactive module designed to improve residents' knowledge and application of key anatomy concepts pertinent to radiotherapy treatment planning was developed, and its effectiveness was assessed.Methods and Materials: The module, based on gynecologic malignancies, was developed in collaboration with a multidisciplinary team of subject matter experts. Subsequently, a multi-centre randomized controlled study was conducted to test the module's effectiveness. Thirty-six radiation oncology residents participated in the study; 1920 were granted access to the module (intervention group), and 17 in the control group relied on traditional methods to acquire their knowledge. Pretests and posttests were administered to all participants. Statistical analysis was carried out using paired t test, analysis of variance, and post hoc tests.Results: The randomized control study revealed that the intervention group's pretest and posttest mean scores were 35% and 52%, respectively, and those of the control group were 37% and 42%, respectively. The mean improvement in test scores was 17% (p < 0.05) for the intervention group and 5% (p = not significant) for the control group. Retrospective pretest and posttest surveys showed a statistically significant change on all measured module objectives.Conclusions: The use of an interactive e-learning teaching module for radiation oncology is an effective method to improve the radiologic anatomy knowledge and treatment planning skills of radiation oncology residents.

Meetings

2012-03-01

March 3-4, 2012 3rd Asian Breast Cancer Congress