International Journal of Radiation Oncology * Biology * Physics - Articles in Press

Role of Positron Emission Tomography-Computed Tomography in the Management of Anal Cancer - Corrected Proof

2012-05-16

Purpose: Pre- and post-treatment staging of anal cancer are often inaccurate. The role of positron emission tomograpy-computed tomography (PET-CT) in anal cancer is yet to be defined. The aim of the study was to compare PET-CT with CT scan, sentinel node biopsy results of inguinal lymph nodes, and anal biopsy results in staging and in follow-up of anal cancer.Methods and Materials: Fifty-three consecutive patients diagnosed with anal cancer underwent PET-CT. Results were compared with computed tomography (CT), performed in 40 patients, and with sentinel node biopsy (SNB) (41 patients) at pretreatment workup. Early follow-up consisted of a digital rectal examination, an anoscopy, a PET-CT scan, and anal biopsies performed at 1 and 3 months after the end of treatment. Data sets were then compared.Results: At pretreatment assessment, anal cancer was identified by PET-CT in 47 patients (88.7%) and by CT in 30 patients (75%). The detection rates rose to 97.9% with PET-CT and to 82.9% with CT (P=.042) when the 5 patients who had undergone surgery prior to this assessment and whose margins were positive at histological examination were censored. Perirectal and/or pelvic nodes were considered metastatic by PET-CT in 14 of 53 patients (26.4%) and by CT in 7 of 40 patients (17.5%). SNB was superior to both PET-CT and CT in detecting inguinal lymph nodes. PET-CT upstaged 37.5% of patients and downstaged 25% of patients. Radiation fields were changed in 12.6% of patients. PET-CT at 3 months was more accurate than PET-CT at 1 month in evaluating outcomes after chemoradiation therapy treatment: sensitivity was 100% vs 66.6%, and specificity was 97.4% vs 92.5%, respectively. Median follow-up was 20.3 months.Conclusions: In this series, PET-CT detected the primary tumor more often than CT. Staging of perirectal/pelvic or inguinal lymph nodes was better with PET-CT. SNB was more accurate in staging inguinal lymph nodes.

A One-Step Cone-Beam CT-Enabled Planning-to-Treatment Model for Palliative Radiotherapy-From Development to Implementation - Corrected Proof

2012-05-16

Purpose: To develop a cone-beam computed tomography (CT)–enabled one-step simulation-to-treatment process for the treatment of bone metastases.Methods and Materials: A three-phase prospective study was conducted. Patients requiring palliative radiotherapy to the spine, mediastinum, or abdomen/pelvis suitable for treatment with simple beam geometry (≤2 beams) were accrued. Phase A established the accuracy of cone-beam CT images for the purpose of gross tumor target volume (GTV) definition. Phase B evaluated the feasibility of implementing the cone-beam CT–enabled planning process at the treatment unit. Phase C evaluated the online cone-beam CT–enabled process for the planning and treatment of patients requiring radiotherapy for bone metastases.Results: Eighty-four patients participated in this study. Phase A (n = 9) established the adequacy of cone-beam CT images for target definition. Phase B (n = 45) established the quality of treatment plans to be adequate for clinical implementation for bone metastases. When the process was applied clinically in bone metastases (Phase C), the degree of overlap between planning computed tomography (PCT) and cone-beam CT for GTV and between PCT and cone-beam CT for treatment field was 82% ± 11% and 97% ± 4%, respectively. The oncologist’s decision to accept the plan under a time-pressured environment remained of high quality, with the cone-beam CT–generated treatment plan delivering at least 90% of the prescribed dose to 100% ± 0% of the cone-beam CT planning target volume (PTV). With the assumption that the PCT PTV is the gold-standard target, the cone-beam CT–generated treatment plan delivered at least 90% and at least 95% of dose to 98% ± 2% and 97% ± 5% of the PCT PTV, respectively. The mean time for the online planning and treatment process was 32.7 ± 4.0 minutes. Patient satisfaction was high, with a trend for superior satisfaction with the cone-beam CT–enabled process.Conclusions: The cone-beam CT–enabled palliative treatment process is feasible and is ready for clinical implementation for the treatment of bone metastases using simple beam geometry, providing a streamlined one-step process toward palliative radiotherapy.

Risk of Radiation Retinopathy in Patients With Orbital and Ocular Lymphoma - Corrected Proof

Megha Kaushik, Jose S. Pulido, Steven E. Schild, Scott Stafford — 2012-05-16

Purpose: Radiation retinopathy is a potential long-term complication of radiation therapy to the orbit. The risk of developing this adverse effect is dose dependent; however, the threshold is unclear. The aim of this study was to identify the risk of developing radiation retinopathy at increasing radiation doses.Methods and Materials: A 40-year retrospective review was performed of patients who received external beam radiation therapy for ocular/orbital non-Hodgkin lymphoma (NHL).Results: Sixty-seven patients who had at least one ophthalmic follow-up examination were included in this study. Most patients (52%) were diagnosed with NHL involving the orbit. Patients received external beam radiation therapy at doses between 1886 and 5400 cGy (mean, 3033 ± 782 cGy). Radiation retinopathy developed in 12% of patients, and the median time to diagnosis was 27 months (range, 15-241months). The mean prescribed radiation dose in patients with retinopathy was 3309 ± 585 cGy, and the estimated retinal dose (derived by reviewing the dosimetry) was 3087 ± 1030 cGy. The incidence of retinopathy increased with dose. The average prescribed daily fractionated dose was higher in patients who developed retinopathy than in patients who did not (mean, 202 cGy vs 180 cGy, respectively; P = .04). More patients with radiation retinopathy had comorbid diabetes mellitus type 2 than patients without retinopathy (P = .015). In our study, the mean visual acuity of the eyes that received radiation was worse than that of the eyes that did not (P = .027). Other postradiotherapy ocular findings included keratitis (6%), dry eyes (39%), and cataract (33%).Conclusions: Radiation retinopathy, a known complication of radiotherapy for orbital tumors, relates to vascular comorbidities and dose. Higher total doses and larger daily fractions (>180 cGy) appear to be related to higher rates of retinopathy. Future larger studies are required to identify a statistically significant threshold for the development of retinopathy.

Predictors of Toxicity After Image-guided High-dose-rate Interstitial Brachytherapy for Gynecologic Cancer - Corrected Proof

Larissa J. Lee, Akila N. Viswanathan — 2012-05-16

Purpose: To identify predictors of grade 3-4 complications and grade 2-4 rectal toxicity after three-dimensional image-guided high-dose-rate (HDR) interstitial brachytherapy for gynecologic cancer.Methods and Materials: Records were reviewed for 51 women (22 with primary disease and 29 with recurrence) treated with HDR interstitial brachytherapy. A single interstitial insertion was performed with image guidance by computed tomography (n = 43) or magnetic resonance imaging (n = 8). The median delivered dose in equivalent 2-Gy fractions was 72.0 Gy (45 Gy for external-beam radiation therapy and 24 Gy for brachytherapy). Toxicity was reported according to the Common Toxicity Criteria for Adverse Events. Actuarial toxicity estimates were calculated by the Kaplan-Meier method.Results: At diagnosis, the median patient age was 62 years and the median tumor size was 3.8 cm. The median D90 and V100 were 71.4 Gy and 89.5%; the median D2cc for the bladder, rectum, and sigmoid were 64.6 Gy, 61.0 Gy, and 52.7 Gy, respectively. The actuarial rates of all grade 3-4 complications at 2 years were 20% gastrointestinal, 9% vaginal, 6% skin, 3% musculoskeletal, and 2% lymphatic. There were no grade 3-4 genitourinary complications and no grade 5 toxicities. Grade 2-4 rectal toxicity was observed in 10 patients, and grade 3-4 complications in 4; all cases were proctitis with the exception of 1 rectal fistula. D2cc for rectum was higher for patients with grade 2-4 (68 Gy vs 57 Gy for grade 0-1, P=.03) and grade 3-4 (73 Gy vs 58 Gy for grade 0-2, P=.02) rectal toxicity. The estimated dose that resulted in a 10% risk of grade 2-4 rectal toxicity was 61.8 Gy (95% confidence interval, 51.5-72.2 Gy).Discussion: Image-guided HDR interstitial brachytherapy results in acceptable toxicity for women with primary or recurrent gynecologic cancer. D2cc for the rectum is a reliable predictor of late rectal complications. Three-dimensional-based treatment planning should be performed to ensure adequate tumor coverage while minimizing the D2cc to the rectum.

No Effect of the Transforming Growth Factor β1 Promoter Polymorphism C-509T on TGFB1 Gene Expression, Protein Secretion, or Cellular Radiosensitivity - Corrected Proof

2012-05-16

Purpose: To study whether the promoter polymorphism (C-509T) affects transforming growth factor β1 gene (TGFB1) expression, protein secretion, and/or cellular radiosensitivity for both human lymphocytes and fibroblasts.Methods and Materials: Experiments were performed with lymphocytes taken either from 124 breast cancer patients or 59 pairs of normal monozygotic twins. We used 15 normal human primary fibroblast strains as controls. The C-509T genotype was determined by polymerase chain reaction-restriction fragment length polymorphism or TaqMan single nucleotide polymorphism (SNP) genotyping assay. The cellular radiosensitivity of lymphocytes was measured by G0/1 assay and that of fibroblasts by colony assay. The amount of extracellular TGFB1 protein was determined by enzyme-linked immunosorbent assay, and TGFB1 expression was assessed via microarray analysis or reverse transcription-polymerase chain reaction.Results: The C-509T genotype was found not to be associated with cellular radiosensitivity, neither for lymphocytes (breast cancer patients, P=.811; healthy donors, P=.181) nor for fibroblasts (P=.589). Both TGFB1 expression and TGFB1 protein secretion showed considerable variation, which, however, did not depend on the C-509T genotype (protein secretion: P=.879; gene expression: lymphocytes, P=.134, fibroblasts, P=.605). There was also no general correlation between TGFB1 expression and cellular radiosensitivity (lymphocytes, P=.632; fibroblasts, P=.573).Conclusion: Our data indicate that any association between the SNP C-509T of TGFB1 and risk of normal tissue toxicity cannot be ascribed to a functional consequence of this SNP, either on the level of gene expression, protein secretion, or cellular radiosensitivity.

Identification and Characterization of a Small Inhibitory Peptide That Can Target DNA-PKcs Autophosphorylation and Increase Tumor Radiosensitivity - Corrected Proof

2012-05-16

Purpose: The DNA protein kinase catalytic subunit (DNA-PKcs) is one of the critical elements involved in the DNA damage repair process. Inhibition of DNA-PKcs results in hypersensitivity to ionizing radiation (IR); therefore, this approach has been explored to develop molecular targeted radiosensitizers. Here, we aimed to develop small inhibitory peptides that could specifically target DNA-PKcs autophosphorylation, a critical step for the enzymatic activation of the kinase in response to IR.Methods and Materials: We generated several small fusion peptides consisting of 2 functional domains, 1 an internalization domain and the other a DNA-PKcs autophosphorylation inhibitory domain. We characterized the internalization, toxicity, and radiosensitization activities of the fusion peptides. Furthermore, we studied the mechanisms of the inhibitory peptides on DNA-PKcs autophosphorylation and DNA repair.Results: We found that among several peptides, the biotin-labeled peptide 3 (BTW3) peptide, which targets DNA-PKcs threonine 2647 autophosphorylation, can abrogate IR-induced DNA-PKcs activation and cause prolonged γ-H2AX focus formation. We demonstrated that BTW3 exposure led to hypersensitivity to IR in DNA-PKcs-proficient cells but not in DNA-PKcs-deficient cells.Conclusions: The small inhibitory peptide BTW3 can specifically target DNA-PKcs autophosphorylation and enhance radiosensitivity; therefore, it can be further developed as a novel class of radiosensitizer.

Dose-Effect Relationship in Chemoradiotherapy for Locally Advanced Rectal Cancer: A Randomized Trial Comparing Two Radiation Doses - Corrected Proof

2012-05-16

Purpose: Locally advanced rectal cancer represents a major therapeutic challenge. Preoperative chemoradiation therapy is considered standard, but little is known about the dose-effect relationship. The present study represents a dose-escalation phase III trial comparing 2 doses of radiation.Methods and Materials: The inclusion criteria were resectable T3 and T4 tumors with a circumferential margin of ≤5 mm on magnetic resonance imaging. The patients were randomized to receive 50.4 Gy in 28 fractions to the tumor and pelvic lymph nodes (arm A) or the same treatment supplemented with an endorectal boost given as high-dose-rate brachytherapy (10 Gy in 2 fractions; arm B). Concomitant chemotherapy, uftoral 300 mg/m2 and L-leucovorin 22.5 mg/d, was added to both arms on treatment days. The primary endpoint was complete pathologic remission. The secondary endpoints included tumor response and rate of complete resection (R0).Results: The study included 248 patients. No significant difference was found in toxicity or surgical complications between the 2 groups. Based on intention to treat, no significant difference was found in the complete pathologic remission rate between the 2 arms (18% and 18%). The rate of R0 resection was different in T3 tumors (90% and 99%; P=.03). The same applied to the rate of major response (tumor regression grade, 1+2), 29% and 44%, respectively (P=.04).Conclusions: This first randomized trial comparing 2 radiation doses indicated that the higher dose increased the rate of major response by 50% in T3 tumors. The endorectal boost is feasible, with no significant increase in toxicity or surgical complications.

Dose Escalation of Total Marrow Irradiation With Concurrent Chemotherapy in Patients With Advanced Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation - Corrected Proof

2012-05-16

Purpose: We have demonstrated that toxicities are acceptable with total marrow irradiation (TMI) at 16 Gy without chemotherapy or TMI at 12 Gy and the reduced intensity regimen of fludarabine/melphalan in patients undergoing hematopoietic cell transplantation (HCT). This article reports results of a study of TMI combined with higher intensity chemotherapy regimens in 2 phase I trials in patients with advanced acute myelogenous leukemia or acute lymphoblastic leukemia (AML/ALL) who would do poorly on standard intent-to-cure HCT regimens.Methods and Materials: Trial 1 consisted of TMI on Days −10 to −6, etoposide (VP16) on Day −5 (60 mg/kg), and cyclophosphamide (CY) on Day −3 (100 mg/kg). TMI dose was 12 (n=3 patients), 13.5 (n=3 patients), and 15 (n=6 patients) Gy at 1.5 Gy twice daily. Trial 2 consisted of busulfan (BU) on Days −12 to −8 (800 μM min), TMI on Days −8 to −4, and VP16 on Day −3 (30 mg/kg). TMI dose was 12 (n=18) and 13.5 (n=2) Gy at 1.5 Gy twice daily.Results: Trial 1 had 12 patients with a median age of 33 years. Six patients had induction failures (IF), and 6 had first relapses (1RL), 9 with leukemia blast involvement of bone marrow ranging from 10%-98%, 5 with circulating blasts (24%-85%), and 2 with chloromas. No dose-limiting toxicities were observed. Eleven patients achieved complete remission at Day 30. With a median follow-up of 14.75 months, 5 patients remained in complete remission from 13.5-37.7 months. Trial 2 had 20 patients with a median age of 41 years. Thirteen patients had IF, and 5 had 1RL, 2 in second relapse, 19 with marrow blasts (3%-100%) and 13 with peripheral blasts (6%-63%). Grade 4 dose-limiting toxicities were seen at 13.5 Gy (stomatitis and hepatotoxicity). Stomatitis was the most frequent toxicity in both trials.Conclusions: TMI dose escalation to 15 Gy is possible when combined with CY/VP16 and is associated with acceptable toxicities and encouraging outcomes. TMI dose escalation is not possible with BU/VP16 due to dose-limiting toxicities. Future efforts will focus on whether further dose escalation with CY/VP16 is safe, with the goal of improving disease control in this high-risk population.

Short-Course Accelerated Radiotherapy in Palliative Treatment of Advanced Pelvic Malignancies: A Phase I Study - Corrected Proof

2012-05-14

Purpose: To define the maximum tolerated dose of a conformal short-course accelerated radiotherapy in patients with symptomatic advanced pelvic cancer.Methods and Materials: A phase I trial in 3 dose-escalation steps was designed: 14 Gy (3.5-Gy fractions), 16 Gy (4-Gy fractions), and 18 Gy (4.5-Gy fractions). The eligibility criteria included locally advanced and/or metastatic pelvic cancer and Eastern Cooperative Oncology Group performance status of ≤3. Treatment was delivered in 2 days with twice-daily fractionation and at least an 8-hour interval. Patients were treated in cohorts of 6-12 to define the maximum tolerated dose. The dose-limiting toxicity was defined as any acute toxicity of grade 3 or greater, using the Radiation Therapy Oncology Group scale. Pain was recorded using a visual analog scale. The effect on quality of life was evaluated according to Cancer Linear Analog Scale (CLAS).Results: Of the 27 enrolled patients, 11 were male and 16 were female, with a median age of 72 years (range 47-86). The primary tumor sites were gynecologic (48%), colorectal (33.5%), and genitourinary (18.5%). The most frequent baseline symptoms were bleeding (48%) and pain (33%). Only grade 1-2 acute toxicities were recorded. No patients experienced dose-limiting toxicity. With a median follow-up time of 6 months (range 3-28), no late toxicities were observed. The overall (complete plus partial) symptom remission was 88.9% (95% confidence interval 66.0%-97.8%). Five patients (41.7%) had complete pain relief, and six (50%) showed >30% visual analog scale reduction. The overall response rate for pain was 91.67% (95% confidence interval 52.4%-99.9%).Conclusions: Conformal short course radiotherapy in twice-daily fractions for 2 consecutive days was well tolerated up to a total dose of 18 Gy. A phase II study is ongoing to confirm the efficacy on symptom control and quality of life indexes.

Regional Normal Lung Tissue Density Changes in Patients Treated With Stereotactic Body Radiation Therapy for Lung Tumors - Corrected Proof

2012-05-14

Purpose: To describe regional lung tissue density changes in normal lung tissue of patients with primary and metastatic lung tumors who received stereotactic body radiation therapy (SBRT).Methods and Materials: A total of 179 post-SBRT follow-up computed tomography (CT) scans of 62 patients who received SBRT between 2003 and 2009 were studied. Median prescription dose was 54 Gy (range, 30-60 Gy) in 3 to 5 fractions. SBRT-induced lung density changes on post-SBRT follow-up CT were evaluated at approximately 3, 6, 12, 18, 24, and 30 months after treatment. Dose-response curves (DRC) were generated for SBRT-induced lung damage by averaging CT number (HU) changes for regions of the lungs receiving the same dose at 5-Gy intervals.Results: For all follow-up interval periods, CT numbers linearly increased with dose until 35 Gy and were constant thereafter. For 3, 18, 24, and 30 months, the rate of relative electron density increase with dose was approximately 0.24% per Gy. At 6 months, the rate was also similar below 20 Gy but then rose to 0.6% per Gy above this threshold. After 6 months, DRCs were mostly time-independent. When split between patients treated with 3 fractions of 12 to 20 Gy (median, 20 Gy; average tumor volume, 12 ± 16 cm3) and with >3 fractions of 6 to 12.5 Gy (median, 9 Gy; average tumor volume, 30 ± 40 cm3), DRCs differed significantly. In both cases, CT changes at 3, 18, 24, and 30 months were identical to those of the population DRC; however, patients who received >3 fractions showed 6-month CT changes that were more than twice those for the group that received 3 fractions.Conclusions: This analysis of SBRT-induced normal lung density changes indicates that lung normal tissue has more pronounced self-limited acute effects than late effects. Differences in acute CT changes following treatments in 3 fractions were considerably less than for treatments in >3 fractions.

Skin-sparing Helical Tomotherapy vs 3D-conformal Radiotherapy for Adjuvant Breast Radiotherapy: In Vivo Skin Dosimetry Study - Corrected Proof

2012-05-14

Purpose: We investigated whether treatment-planning system (TPS)-calculated dose accurately reflects skin dose received for patients receiving adjuvant breast radiotherapy (RT) with standard three-dimensional conformal RT (3D-CRT) or skin-sparing helical tomotherapy (HT).Methods and Materials: Fifty patients enrolled in a randomized controlled trial investigating acute skin toxicity from adjuvant breast RT with 3D-CRT compared to skin-sparing HT, where a 5-mm strip of ipsilateral breast skin was spared. Thermoluminescent dosimetry or optically stimulated luminescence measurements were made in multiple locations and were compared to TPS-calculated doses. Skin dosimetric parameters and acute skin toxicity were recorded in these patients.Results: With HT there was a significant correlation between calculated and measured dose in the medial and lateral ipsilateral breast (r = 0.67, P<.001; r = 0.44, P=.03, respectively) and the medial and central contralateral breast (r = 0.73, P<.001; r = 0.88, P<.001, respectively). With 3D-CRT there was a significant correlation in the medial and lateral ipsilateral breast (r = 0.45, P=.03; r = 0.68, P<.001, respectively); the medial and central contralateral breast (r = 0.62, P=.001; r = 0.86, P<.001, respectively); and the mid neck (r = 0.42, P=.04, respectively). On average, HT-calculated dose overestimated the measured dose by 14%; 3D-CRT underestimated the dose by 0.4%. There was a borderline association between highest measured skin dose and moist desquamation (P=.05). Skin-sparing HT had greater skin homogeneity (homogeneity index of 1.39 vs 1.65, respectively; P=.005) than 3D-CRT plans. HT plans had a lower skinV50 (1.4% vs 5.9%, respectively; P=.001) but higher skinV40 and skinV30 (71.7% vs 64.0%, P=.02; and 99.0% vs 93.8%, P=.001, respectively) than 3D-CRT plans.Conclusion: The 3D-CRT TPS more accurately reflected skin dose than the HT TPS, which tended to overestimate dose received by 14% in patients receiving adjuvant breast RT.

Five-year Local Control in a Phase II Study of Hypofractionated Intensity Modulated Radiation Therapy With an Incorporated Boost for Early Stage Breast Cancer - Corrected Proof

2012-05-14

Purpose: Conventional radiation fractionation of 1.8-2 Gy per day for early stage breast cancer requires daily treatment for 6-7 weeks. We report the 5-year results of a phase II study of intensity modulated radiation therapy (IMRT), hypofractionation, and incorporated boost that shortened treatment time to 4 weeks.Methods and Materials: The study design was phase II with a planned accrual of 75 patients. Eligibility included patients aged ≥18 years, Tis-T2, stage 0-II, and breast conservation. Photon IMRT and an incorporated boost was used, and the whole breast received 2.25 Gy per fraction for a total of 45 Gy, and the tumor bed received 2.8 Gy per fraction for a total of 56 Gy in 20 treatments over 4 weeks. Patients were followed every 6 months for 5 years.Results: Seventy-five patients were treated from December 2003 to November 2005. The median follow-up was 69 months. Median age was 52 years (range, 31-81). Median tumor size was 1.4 cm (range, 0.1-3.5). Eighty percent of tumors were node negative; 93% of patients had negative margins, and 7% of patients had close (>0 and <2 mm) margins; 76% of cancers were invasive ductal type: 15% were ductal carcinoma in situ, 5% were lobular, and 4% were other histology types. Twenty-nine percent of patients 29% had grade 3 carcinoma, and 20% of patients had extensive in situ carcinoma; 11% of patients received chemotherapy, 36% received endocrine therapy, 33% received both, and 20% received neither. There were 3 instances of local recurrence for a 5-year actuarial rate of 2.7%.Conclusions: This 4-week course of hypofractionated radiation with incorporated boost was associated with excellent local control, comparable to historical results of 6-7 weeks of conventional whole-breast fractionation with sequential boost.

Optimal Timing for Assessment of Tumor Response to Neoadjuvant Chemoradiation in Patients With Rectal Cancer: Do All Patients Benefit From Waiting Longer Than 6 Weeks? - Corrected Proof

2012-05-14

Purpose: To estimate the metabolic activity of rectal cancers at 6 and 12 weeks after completion of chemoradiation therapy (CRT) by 2-[fluorine-18] fluoro-2-deoxy-d-glucose-labeled positron emission tomography/computed tomography ([18FDG]PET/CT) imaging and correlate with response to CRT.Methods and Materials: Patients with cT2-4N0-2M0 distal rectal adenocarcinoma treated with long-course neoadjuvant CRT (54 Gy, 5-fluouracil-based) were prospectively studied (ClinicalTrials.org identifier NCT00254683). All patients underwent 3 PET/CT studies (at baseline and 6 and 12 weeks from CRT completion). Clinical assessment was at 12 weeks. Maximal standard uptake value (SUVmax) of the primary tumor was measured and recorded at each PET/CT study after 1 h (early) and 3 h (late) from 18FDG injection. Patients with an increase in early SUVmax between 6 and 12 weeks were considered “bad” responders and the others as “good” responders.Results: Ninety-one patients were included; 46 patients (51%) were “bad” responders, whereas 45 (49%) patients were “good” responders. “Bad” responders were less likely to develop complete clinical response (6.5% vs. 37.8%, respectively; P=.001), less likely to develop significant histological tumor regression (complete or near-complete pathological response; 16% vs. 45%, respectively; P=.008) and exhibited greater final tumor dimension (4.3 cm vs. 3.3 cm; P=.03). Decrease between early (1 h) and late (3 h) SUVmax at 6-week PET/CT was a significant predictor of “good” response (accuracy of 67%).Conclusions: Patients who developed an increase in SUVmax after 6 weeks were less likely to develop significant tumor downstaging. Early-late SUVmax variation at 6-week PET/CT may help identify these patients and allow tailored selection of CRT-surgery intervals for individual patients.

A System for Continual Quality Improvement of Normal Tissue Delineation for Radiation Therapy Treatment Planning - Corrected Proof

2012-05-14

Purpose: To implement the “plan-do-check-act” (PDCA) cycle for the continual quality improvement of normal tissue contours used for radiation therapy treatment planning.Methods and Materials: The CT scans of patients treated for tumors of the brain, head and neck, thorax, pancreas and prostate were selected for this study. For each scan, a radiation oncologist and a diagnostic radiologist, outlined the normal tissues (“gold” contours) using Radiation Therapy Oncology Group (RTOG) guidelines. A total of 30 organs were delineated. Independently, 5 board-certified dosimetrists and 1 trainee then outlined the same organs. Metrics used to compare the agreement between the dosimetrists' contours and the gold contours included the Dice Similarity Coefficient (DSC), and a penalty function using distance to agreement. Based on these scores, dosimetrists were re-trained on those organs in which they did not receive a passing score, and they were subsequently re-tested.Results: Passing scores were achieved on 19 of 30 organs evaluated. These scores were correlated to organ volume. For organ volumes <8 cc, the average DSC was 0.61 vs organ volumes ≥8 cc, for which the average DSC was 0.91 (P=.005). Normal tissues that had the lowest scores included the lenses, optic nerves, chiasm, cochlea, and esophagus. Of the 11 organs that were considered for re-testing, 10 showed improvement in the average score, and statistically significant improvement was noted in more than half of these organs after education and re-assessment.Conclusions: The results of this study indicate the feasibility of applying the PDCA cycle to assess competence in the delineation of individual organs, and to identify areas for improvement. With testing, guidance, and re-evaluation, contouring consistency can be obtained across multiple dosimetrists. Our expectation is that continual quality improvement using the PDCA approach will ensure more accurate treatments and dose assessment in radiotherapy treatment planning and delivery.

Inhibition of Protease-activated Receptor 1 Ameliorates Intestinal Radiation Mucositis in a Preclinical Rat Model - Corrected Proof

Junru Wang, Ashwini Kulkarni, Madhu Chintala, Louis M. Fink, Martin Hauer-Jensen — 2012-05-14

Purpose: To determine, using a specific small-molecule inhibitor of protease-activated receptor 1 (PAR1) signaling, whether the beneficial effect of thrombin inhibition on radiation enteropathy development is due to inhibition of blood clotting or to cellular (PAR1-mediated) thrombin effects.Methods and Materials: Rats underwent fractionated X-irradiation (5 Gy × 9) of a 4-cm small-bowel segment. Early radiation toxicity was evaluated in rats receiving PAR1 inhibitor (SCH602539, 0, 10, or 15 μg/kg/d) from 1 day before to 2 weeks after the end of irradiation. The effect of PAR1 inhibition on development of chronic intestinal radiation fibrosis was evaluated in animals receiving SCH602539 (0, 15, or 30 μg/kg/d) until 2 weeks after irradiation, or continuously until termination of the experiment 26 weeks after irradiation.Results: Blockade of PAR1 ameliorated early intestinal toxicity, with reduced overall intestinal radiation injury (P=.002), number of myeloperoxidase-positive (P=.03) and proliferating cell nuclear antigen-positive (P=.04) cells, and collagen III accumulation (P=.005). In contrast, there was no difference in delayed radiation enteropathy in either the 2- or 26-week administration groups.Conclusion: Pharmacological blockade of PAR1 seems to reduce early radiation mucositis but does not affect the level of delayed intestinal radiation fibrosis. Early radiation enteropathy is related to activation of cellular thrombin receptors, whereas platelet activation or fibrin formation may play a greater role in the development of delayed toxicity. Because of the favorable side-effect profile, PAR1 blockade should be further explored as a method to ameliorate acute intestinal radiation toxicity in patients undergoing radiotherapy for cancer and to protect first responders and rescue personnel in radiologic/nuclear emergencies.

Monitoring of Circulating Tumor Cells and Their Expression of EGFR/Phospho-EGFR During Combined Radiotherapy Regimens in Locally Advanced Squamous Cell Carcinoma of the Head and Neck - Corrected Proof

2012-05-14

Purpose: The numbers of circulating tumor cells (CTCs) and their expression/activation of epidermal growth factor receptor (EGFR) during the course of combined chemo- or bioradiotherapy regimens as potential biomarkers of treatment efficacy in squamous cell carcinoma of the head and neck (SCCHN) were determined.Methods and Materials: Peripheral blood samples from SCCHN patients with locally advanced stage IVA/B disease who were treated with concurrent radiochemotherapy or induction chemotherapy followed by bioradiation with cetuximab were included in this study. Using flow cytometry, the absolute number of CTCs per defined blood volume as well as their expression of EGFR and its phosphorylated form (pEGFR) during the course of treatment were assessed.Results: Before treatment, we detected ≥1 CTC per 3.75 mL blood in 9 of 31 patients (29%). Basal expression of EGFR was detected in 100% and pEGFR in 55% of the CTC+ cases. The frequency of CTC detection was not influenced by induction chemotherapy. However, the number of CTC+ samples significantly increased after radiotherapy. This radiation-induced increase in CTC numbers was less pronounced when radiotherapy was combined with cetuximab compared to its combination with cisplatin/5-fluorouracil. The former treatment regimen was also more effective in reducing pEGFR expression in CTCs.Conclusions: Definitive radiotherapy regimens of locally advanced SCCHN can increase the number of CTCs and might thus contribute to a systemic spread of tumor cells. Further studies are needed to evaluate the predictive value of the radiation-induced increase in CTC numbers and the persistent activation of the EGFR signalling pathway in individual CTC+ cases.

[18F]fluoromisonidazole and a New PET System With Semiconductor Detectors and a Depth of Interaction System for Intensity Modulated Radiation Therapy for Nasopharyngeal Cancer - Corrected Proof

2012-05-14

Purpose: The impact of a new type of positron emission tomography (New PET) with semiconductor detectors using 18F-labeled fluoromisonidazole (FMISO)-guided intensity modulated radiation therapy (IMRT) was compared with a state-of-the-art PET/computed tomography (PET/CT) system in nasopharyngeal cancer (NPC) patients.Methods and Materials: Twenty-four patients with non-NPC malignant tumors (control group) and 16 patients with NPC were subjected to FMISO-PET. The threshold of the tumor-to-muscle (T/M) ratio in each PET scan was calculated. The hypoxic volume within the gross tumor volume (GTVh) was determined using each PET (NewPETGTVh and PET/CTGTVh, respectively). Dose escalation IMRT plans prescribing 84 Gy to each GTVh were carried out.Results: The threshold of the T/M ratio was 1.35 for New PET and 1.23 for PET/CT. The mean volume of NewPETGTVh was significantly smaller than that of PET/CTGTVh (1.5 ± 1.6 cc vs 4.7 ± 4.6 cc, respectively; P=.0020). The dose escalation IMRT plans using New PET were superior in dose distribution to those using PET/CT. Dose escalation was possible in all 10 New PET-guided plans but not in 1 PET/CT-guided plan, because the threshold dose to the brainstem was exceeded.Conclusions: New PET was found to be useful for accurate dose escalation in FMISO-guided IMRT for patients with NPC.

Normal Tissue Anatomy for Oropharyngeal Cancer: Contouring Variability and Its Impact on Optimization - Corrected Proof

Mary Feng, Candan Demiroz, Karen A. Vineberg, Avraham Eisbruch, James M. Balter — 2012-05-14

Purpose: To evaluate the variability of organ at risk (OAR) delineation and the resulting impact on intensity modulated radiation therapy (IMRT) treatment plan optimization in head-and-neck cancer.Methods and Materials: An expert panel of 3 radiation oncologists jointly delineated OARs, including the parotid and submandibular glands (SM), pharyngeal constrictors (PC), larynx, and glottis (GL), in 10 patients with advanced oropharynx cancer in 3 contouring sessions, spaced at least 1 week apart. Contour variability and uncertainty, as well as their dosimetric impact on IMRT planning for each case, were assessed.Results: The mean difference in total volume for each OAR was 1 cm3 (σ 0.5 cm3). Mean fractional overlap was 0.7 (σ 0.1) and was highest (0.8) for the larynx and bilateral SMs and parotids and lowest (0.5) for PC. There were considerable spatial differences in contours, with the ipsilateral parotid and PC displaying the most variability (0.9 cm), which was most prominent in cases in which tumors obliterated fat planes. Both SMs and GL had the smallest differences (0.5 cm). The mean difference in OAR dose was 0.9 Gy (range 0.6-1.1 Gy, σ 0.1 Gy), with the smallest difference for GL and largest for both SMs and the larynx.Conclusions: Despite substantial difference in OAR contours, optimization was barely affected, with a 0.9-Gy mean difference between optimizations, suggesting relative insensitivity of dose distributions for IMRT of oropharynx cancer to the extent of OARs.

Normal Tissue Complication Probability Modeling of Radiation-Induced Hypothyroidism After Head-and-Neck Radiation Therapy - Corrected Proof

2012-05-14

Purpose: To determine the dose-response relationship of the thyroid for radiation-induced hypothyroidism in head-and-neck radiation therapy, according to 6 normal tissue complication probability models, and to find the best-fit parameters of the models.Methods and Materials: Sixty-five patients treated with primary or postoperative radiation therapy for various cancers in the head-and-neck region were prospectively evaluated. Patient serum samples (tri-iodothyronine, thyroxine, thyroid-stimulating hormone [TSH], free tri-iodothyronine, and free thyroxine) were measured before and at regular time intervals until 1 year after the completion of radiation therapy. Dose-volume histograms (DVHs) of the patients' thyroid gland were derived from their computed tomography (CT)-based treatment planning data. Hypothyroidism was defined as increased TSH (subclinical hypothyroidism) or increased TSH in combination with decreased free thyroxine and thyroxine (clinical hypothyroidism). Thyroid DVHs were converted to 2 Gy/fraction equivalent doses using the linear-quadratic formula with α/β = 3 Gy. The evaluated models included the following: Lyman with the DVH reduced to the equivalent uniform dose (EUD), known as LEUD; Logit-EUD; mean dose; relative seriality; individual critical volume; and population critical volume models. The parameters of the models were obtained by fitting the patients' data using a maximum likelihood analysis method. The goodness of fit of the models was determined by the 2-sample Kolmogorov-Smirnov test. Ranking of the models was made according to Akaike's information criterion.Results: Twenty-nine patients (44.6%) experienced hypothyroidism. None of the models was rejected according to the evaluation of the goodness of fit. The mean dose model was ranked as the best model on the basis of its Akaike's information criterion value. The D50 estimated from the models was approximately 44 Gy.Conclusions: The implemented normal tissue complication probability models showed a parallel architecture for the thyroid. The mean dose model can be used as the best model to describe the dose-response relationship for hypothyroidism complication.

Hearing Outcomes After Stereotactic Radiosurgery for Unilateral Intracanalicular Vestibular Schwannomas: Implication of Transient Volume Expansion - Corrected Proof

2012-05-14

Purpose: We evaluated the prognostic factors for hearing outcomes after stereotactic radiosurgery (SRS) for unilateral sporadic intracanalicular vestibular schwannomas (IC-VSs) as a clinical homogeneous group of VSs.Methods and Materials: Sixty consecutive patients with unilateral sporadic IC-VSs, defined as tumors in the internal acoustic canal, and serviceable hearing (Gardner-Roberson grade 1 or 2) were treated with SRS as an initial treatment. The mean tumor volume was 0.34 ± 0.03 cm3 (range, 0.03-1.00 cm3), and the mean marginal dose was 12.2 ± 0.1 Gy (range, 11.5-13.0 Gy). The median follow-up duration was 62 months (range, 36-141 months).Results: The actuarial rates of serviceable hearing preservation were 70%, 63%, and 55% at 1, 2, and 5 years after SRS, respectively. In multivariate analysis, transient volume expansion of ≥20% from initial tumor size was a statistically significant risk factor for loss of serviceable hearing and hearing deterioration (increase of pure tone average ≥20 dB) (odds ratio = 7.638; 95% confidence interval, 2.317-25.181; P=.001 and odds ratio = 3.507; 95% confidence interval, 1.228-10.018; P=.019, respectively). The cochlear radiation dose did not reach statistical significance.Conclusions: Transient volume expansion after SRS for VSs seems to be correlated with hearing deterioration when defined properly in a clinically homogeneous group of patients.

Insufficiency Fractures After Pelvic Radiation Therapy for Uterine Cervical Cancer: An Analysis of Subjects in a Prospective Multi-institutional Trial, and Cooperative Study of the Japan Radiation Oncology Group (JAROG) and Japanese Radiation Oncology Study Group (JROSG) - Corrected Proof

2012-05-14

Purpose: To investigate pelvic insufficiency fractures (IF) after definitive pelvic radiation therapy for early-stage uterine cervical cancer, by analyzing subjects of a prospective, multi-institutional study.Materials and Methods: Between September 2004 and July 2007, 59 eligible patients were analyzed. The median age was 73 years (range, 37-84 years). The International Federation of Gynecologic Oncology and Obstetrics stages were Ib1 in 35, IIa in 12, and IIb in 12 patients. Patients were treated with the constant method, which consisted of whole-pelvic external-beam radiation therapy of 50 Gy/25 fractions and high-dose-rate intracavitary brachytherapy of 24 Gy/4 fractions without chemotherapy. After radiation therapy the patients were evaluated by both pelvic CT and pelvic MRI at 3, 6, 12, 18, and 24 months. Diagnosis of IF was made when the patients had both CT and MRI findings, neither recurrent tumor lesions nor traumatic histories. The CT findings of IF were defined as fracture lines or sclerotic linear changes in the bones, and MRI findings of IF were defined as signal intensity changes in the bones, both on T1- and T2-weighted images.Results: The median follow-up was 24 months. The 2-year pelvic IF cumulative occurrence rate was 36.9% (21 patients). Using Common Terminology Criteria for Adverse Events version 3.0, grade 1, 2, and 3 IF were seen in 12 (21%), 6 (10%), and 3 patients (5%), respectively. Sixteen patients had multiple fractures, so IF were identified at 44 sites. The pelvic IF were frequently seen at the sacroileal joints (32 sites, 72%). Nine patients complained of pain. All patients' pains were palliated by rest or non-narcotic analgesic drugs. Higher age (>70 years) and low body weight (<50 kg) were thought to be risk factors for pelvic IF (P=.007 and P=.013, Cox hazard test).Conclusions: Cervical cancer patients with higher age and low body weight may be at some risk for the development of pelvic IF after pelvic radiation therapy.

Predicting Pneumonitis Risk: A Dosimetric Alternative to Mean Lung Dose - Corrected Proof

2012-05-14

Purpose: To determine whether the association between mean lung dose (MLD) and risk of severe (grade ≥3) radiation pneumonitis (RP) depends on the dose distribution pattern to normal lung among patients receiving 3-dimensional conformal radiation therapy for non-small-cell lung cancer.Methods and Materials: Three cohorts treated with different beam arrangements were identified. One cohort (2-field boost [2FB]) received 2 parallel-opposed (anteroposterior-posteroanterior) fields per fraction initially, followed by a sequential boost delivered using 2 oblique beams. The other 2 cohorts received 3 or 4 straight fields (3FS and 4FS, respectively), ie, all fields were irradiated every day. The incidence of severe RP was plotted against MLD in each cohort, and data were analyzed using the Lyman-Kutcher-Burman (LKB) model.Results: The incidence of grade ≥3 RP rose more steeply as a function of MLD in the 2FB cohort (N=120) than in the 4FS cohort (N=138), with an intermediate slope for the 3FS group (N=99). The estimated volume parameter from the LKB model was n=0.41 (95% confidence interval, 0.15-1.0) and led to a significant improvement in fit (P=.05) compared to a fit with volume parameter fixed at n=1 (the MLD model). Unlike the MLD model, the LKB model with n=0.41 provided a consistent description of the risk of severe RP in all three cohorts (2FB, 3FS, 4FS) simultaneously.Conclusions: When predicting risk of grade ≥3 RP, the mean lung dose does not adequately take into account the effects of high doses. Instead, the effective dose, computed from the LKB model using volume parameter n=0.41, may provide a better dosimetric parameter for predicting RP risk. If confirmed, these findings support the conclusion that for the same MLD, high doses to small lung volumes (“a lot to a little”) are worse than low doses to large volumes (“a little to a lot”).

106Ruthenium Plaque Therapy (RPT) for Retinoblastoma - Corrected Proof

2012-05-11

Purpose: To evaluate the effectiveness of episcleral 106ruthenium plaque therapy (RPT) in the management of retinoblastoma.Methods and Materials: One hundred one RPTs were retrospectively analyzed that were performed in 90 eyes of 85 patients with retinoblastoma at National Cancer Center Hospital between 1998 and 2008. Each RPT had a corresponding tumor and 101 tumors were considered in the analysis of local control. Median follow-up length was 72.8 months. Median patient age at the RPT was 28 months. Median prescribed doses at reference depth and outer surface of the sclera were 47.4 Gy and 162.3 Gy, respectively.Results: Local control rate (LCR) and ocular retention rate (ORR) at 2 years were 33.7% and 58.7%, respectively. Unilateral disease, International Classification of Retinoblastoma group C or more advanced at the first presentation or at the time of RPT, vitreous and/or subretinal seeding, tumor size greater than 5 disc diameter (DD), reference depth greater than 5 mm, dose rate at reference depth lower than 0.7 Gy/hour, dose at the reference depth lower than 35 Gy, and (biologically effective dose with an α/β ratio of 10 Gy) at the reference depth lower than 40 Gy10 were associated with unfavorable LCR. Two patients died of metastatic disease. Radiation complications included retinal detachment in 12 eyes (13.3%), proliferative retinopathy in 6 (6.7%), rubeosis iris in 2 (2.2%), and posterior subcapsular cataract in 23 (25.6%).Conclusion: RPT is an effective eye-preserving treatment for retinoblastoma.

A New Model for Predicting Acute Mucosal Toxicity in Head-and-Neck Cancer Patients Undergoing Radiotherapy With Altered Schedules - Corrected Proof

2012-05-11

Purpose: One of the worst radiation-induced acute effects in treating head-and-neck (HN) cancer is grade 3 or higher acute (oral and pharyngeal) mucosal toxicity (AMT), caused by the killing/depletion of mucosa cells. Here we aim to testing a predictive model of the AMT in HN cancer patients receiving different radiotherapy schedules.Methods and Materials: Various radiotherapeutic schedules have been reviewed and classified as tolerable or intolerable based on AMT severity. A modified normal tissue complication probability (NTCP) model has been investigated to describe AMT data in radiotherapy regimens, both conventional and altered in dose and overall treatment time (OTT). We tested the hypothesis that such a model could also be applied to identify intolerable treatment and to predict AMT. This AMT NTCP model has been compared with other published predictive models to identify schedules that are either tolerable or intolerable. The area under the curve (AUC) was calculated for all models, assuming treatment tolerance as the gold standard. The correlation between AMT and the predicted toxicity rate was assessed by a Pearson correlation test.Results: The AMT NTCP model was able to distinguish between acceptable and intolerable schedules among the data available for the study (AUC = 0.84, 95% confidence interval = 0.75-0.92). In the equivalent dose at 2 Gy/fraction (EQD2) vs OTT space, the proposed model shows a trend similar to that of models proposed by other authors, but was superior in detecting some intolerable schedules. Moreover, it was able to predict the incidence of ≥G3 AMT.Conclusion: The proposed model is able to predict ≥G3 AMT after HN cancer radiotherapy, and could be useful for designing altered/hypofractionated schedules to reduce the incidence of AMT.

Are We Ready for Positron Emission Tomography/Computed Tomography–based Target Volume Definition in Lymphoma Radiation Therapy - Corrected Proof

Kheng-Wei Yeoh, N. George Mikhaeel — 2012-05-11

Fluorine-18 fluorodeoxyglucose (FDG)-positron emission tomography (PET)/computed tomography (CT) has become indispensable for the clinical management of lymphomas. With consistent evidence that it is more accurate than anatomic imaging in the staging and response assessment of many lymphoma subtypes, its utility continues to increase. There have therefore been efforts to incorporate PET/CT data into radiation therapy decision making and in the planning process. Further, there have also been studies investigating target volume definition for radiation therapy using PET/CT data. This article will critically review the literature and ongoing studies on the above topics, examining the value and methods of adding PET/CT data to the radiation therapy treatment algorithm. We will also discuss the various challenges and the areas where more evidence is required.

Contribution of 68Ga-DOTATOC PET/CT to Target Volume Delineation of Skull Base Meningiomas Treated With Stereotactic Radiation Therapy - Corrected Proof

2012-05-11

Purpose: To investigate the potential impact of 68Ga-DOTATOC positron emission tomography (68Ga-DOTATOC-PET) in addition to magnetic resonance imaging (MRI) and computed tomography (CT) for retrospectively assessing the gross tumor volume (GTV) delineation of meningiomas of the skull base in patients treated with fractionated stereotactic radiation therapy (FSRT).Methods and Materials: The study population consisted of 48 patients with 54 skull base meningiomas, previously treated with FSRT. After scans were coregistered, the GTVs were first delineated with MRI and CT data (GTVMRI/CT) and then by PET (GTVPET) data. The overlapping regions of both datasets resulted in the GTVcommon, which was enlarged to the GTVfinal by adding volumes defined by only one of the complementary modalities (GTVMRI/CT-added or GTVPET-added). We then evaluated the contribution of conventional imaging modalities (MRI, CT) and 68Ga-DOTATOC-PET to the GTVfinal, which was used for planning purposes.Results: Forty-eight of the 54 skull base lesions in 45 patients showed increased 68Ga-DOTATOC uptake and were further analyzed. The mean GTVMRI/CT and GTVPET were approximately 21 cm3 and 25 cm3, with a common volume of approximately 15 cm3. PET contributed a mean additional GTV of approximately 1.5 cm3 to the common volume (16% ± 34% of the GTVcommon). Approximately 4.5 cm3 of the GTVMRI/CT was excluded from the contribution to the common volume. The resulting mean GTVfinal was significantly smaller than both the GTVMRI/CT and the GTVPET. Compared with the initial GTVMRI/CT, the addition of 68Ga-DOTATOC-PET resulted in more than 10% modification of the size of the GTVfinal in 32 (67%) meningiomasConclusions: 68Ga-DOTATOC-PET/CT seems to improve the target volume delineation in skull base meningiomas, often leading to a reduction of GTV compared with results from conventional imaging (MRI and CT).

Prognostic Value of Molecular Subtypes, Ki67 Expression and Impact of Postmastectomy Radiation Therapy in Breast Cancer Patients With Negative Lymph Nodes After Mastectomy - Corrected Proof

Jessica Selz, Denise Stevens, Ludivine Jouanneau, Alain Labib, Romuald Le Scodan — 2012-05-09

Purpose: To determine whether Ki67 expression and breast cancer subtypes could predict locoregional recurrence (LRR) and influence the postmastectomy radiotherapy (PMRT) decision in breast cancer (BC) patients with pathologic negative lymph nodes (pN0) after modified radical mastectomy (MRM).Methods and Materials: A total of 699 BC patients with pN0 status after MRM, treated between 2001 and 2008, were identified from a prospective database in a single institution. Tumors were classified by intrinsic molecular subtype as luminal A or B, HER2+, and triple-negative (TN) using estrogen, progesterone, and HER2 receptors. Multivariate Cox analysis was used to determine the risk of LRR associated with intrinsic subtypes and Ki67 expression, adjusting for known prognostic factors.Results: At a median follow-up of 56 months, 17 patients developed LRR. Five-year LRR-free survival and overall survival in the entire population were 97%, and 94.7%, respectively, with no difference between the PMRT (n=191) and no-PMRT (n=508) subgroups. No constructed subtype was associated with an increased risk of LRR. Ki67 >20% was the only independent prognostic factor associated with increased LRR (hazard ratio, 4.18; 95% CI, 1.11-15.77; P<.0215). However, PMRT was not associated with better locoregional control in patients with proliferative tumors.Conclusions: Ki67 expression but not molecular subtypes are predictors of locoregional recurrence in breast cancer patients with negative lymph nodes after MRM. The benefit of adjuvant RT in patients with proliferative tumors should be further investigated in prospective studies.

Eliminating Inconsistencies in Simulation and Treatment Planning Orders in Radiation Therapy - Corrected Proof

2012-05-09

Purpose: To identify deficiencies with simulation and treatment planning orders and to develop corrective measures to improve safety and quality.Methods and Materials: At Washington University, the DMAIIC formalism is used for process management, whereby the process is understood as comprising Define, Measure, Analyze, Improve, Implement, and Control activities. Two complementary tools were used to provide quantitative assessments: failure modes and effects analysis and reported event data. The events were classified by the user according to severity. The event rates (ie, number of events divided by the number of opportunities to generate an event) related to simulation and treatment plan orders were determined.Results: We analyzed event data from the period 2008-2009 to design an intelligent SIMulation and treatment PLanning Electronic (SIMPLE) order system. Before implementation of SIMPLE, event rates of 0.16 (420 of 2558) for a group of physicians that were subsequently used as a pilot group and 0.13 (787 of 6023) for all physicians were obtained. An interdisciplinary group evaluated and decided to replace the Microsoft Word-based form with a Web-based order system. This order system has mandatory fields and context-sensitive logic, an ability to create templates, and enables an automated process for communication of orders through an enterprise management system. After the implementation of the SIMPLE order, the event rate decreased to 0.09 (96 of 1001) for the pilot group and to 0.06 (145 of 2140) for all physicians (P<.0001). The average time to complete the SIMPLE form was 3 minutes, as compared with 7 minutes for the Word-based form. The number of severe events decreased from 10.7% (45 of 420) and 12.1% (96 of 787) to 6.2% (6 of 96) and 10.3% (15 of 145) for the pilot group and all physicians, respectively.Conclusions: There was a dramatic reduction in the total and the number of potentially severe events through use of the SIMPLE system. In addition, the order process has become more efficient and reliable.

A Multiphase Validation of Atlas-Based Automatic and Semiautomatic Segmentation Strategies for Prostate MRI - Corrected Proof

2012-05-09

Purpose: To perform a rigorous technological assessment and statistical validation of a software technology for anatomic delineations of the prostate on MRI datasets.Methods and Materials: A 3-phase validation strategy was used. Phase I consisted of anatomic atlas building using 100 prostate cancer MRI data sets to provide training data sets for the segmentation algorithms. In phase II, 2 experts contoured 15 new MRI prostate cancer cases using 3 approaches (manual, N points, and region of interest). In phase III, 5 new physicians with variable MRI prostate contouring experience segmented the same 15 phase II datasets using 3 approaches: manual, N points with no editing, and full autosegmentation with user editing allowed. Statistical analyses for time and accuracy (using Dice similarity coefficient) endpoints used traditional descriptive statistics, analysis of variance, analysis of covariance, and pooled Student t test.Results: In phase I, average (SD) total and per slice contouring time for the 2 physicians was 228 (75), 17 (3.5), 209 (65), and 15 seconds (3.9), respectively. In phase II, statistically significant differences in physician contouring time were observed based on physician, type of contouring, and case sequence. The N points strategy resulted in superior segmentation accuracy when initial autosegmented contours were compared with final contours. In phase III, statistically significant differences in contouring time were observed based on physician, type of contouring, and case sequence again. The average relative timesaving for N points and autosegmentation were 49% and 27%, respectively, compared with manual contouring. The N points and autosegmentation strategies resulted in average Dice values of 0.89 and 0.88, respectively. Pre- and postedited autosegmented contours demonstrated a higher average Dice similarity coefficient of 0.94.Conclusion: The software provided robust contours with minimal editing required. Observed time savings were seen for all physicians irrespective of experience level and baseline manual contouring speed.

Sexual Functioning Among Endometrial Cancer Patients Treated With Adjuvant High-Dose-Rate Intra-Vaginal Radiation Therapy - Corrected Proof

2012-05-09

Purpose: We used the Female Sexual Function Index (FSFI) to investigate the prevalence of sexual dysfunction (SD) and factors associated with diminished sexual functioning in early stage endometrial cancer (EC) patients treated with simple hysterectomy and adjuvant brachytherapy.Methods and Materials: A cohort of 104 patients followed in a radiation oncology clinic completed questionnaires to quantify current levels of sexual functioning. The time interval between hysterectomy and questionnaire completion ranged from <6 months to >5 years. Multivariate regression was performed using the FSFI as a continuous variable (score range, 1.2-35.4). SD was defined as an FSFI score of <26, based on the published validation study.Results: SD was reported by 81% of respondents. The mean (± standard deviation) domain scores in order of highest-to-lowest functioning were: satisfaction, 2.9 (±2.0); orgasm, 2.5 (±2.4); desire, 2.4 (±1.3); arousal, 2.2 (±2.0); dryness, 2.1 (±2.1); and pain, 1.9 (±2.3). Compared to the index population in which the FSFI cut-score was validated (healthy women ages 18-74), all scores were low. Compared to published scores of a postmenopausal population, scores were not statistically different. Multivariate analysis isolated factors associated with lower FSFI scores, including having laparotomy as opposed to minimally invasive surgery (effect size, −7.1 points; 95% CI, −11.2 to −3.1; P<.001), lack of vaginal lubricant use (effect size, −4.4 points; 95% CI, −8.7 to −0.2, P=.040), and short time interval (<6 months) from hysterectomy to questionnaire completion (effect size, −4.6 points; 95% CI, −9.3-0.2; P=.059).Conclusions: The rate of SD, as defined by an FSFI score <26, was prevalent. The postmenopausal status of EC patients alone is a known risk factor for SD. Additional factors associated with poor sexual functioning following treatment for EC included receipt of laparotomy and lack of vaginal lubricant use.

Conformal Postoperative Radiotherapy in Patients With Positive Resection Margins and/or pT3-4 Prostate Adenocarcinoma - Corrected Proof

2012-05-09

Purpose: To evaluate outcome and toxicity of high-dose conformal radiotherapy (RT) after radical prostatectomy.Methods and Materials: Between August 1998 and December 2007, 182 consecutive patients with positive resection margins and/or pT3-4, node-negative prostate adenocarcinoma underwent postoperative conformal RT. The prescribed median dose to the prostate/seminal vesicle bed was 66.6 Gy (range 50-70). Hormone therapy (a luteinizing hormone-releasing hormone analogue and/or antiandrogen) was administered to 110/182 (60.5%) patients with high-risk features. Biochemical relapse was defined as an increase of more than 0.2 ng/mL over the lowest postoperative prostate-specific antigen (PSA) value measured on 3 occasions, each at least 2 weeks apart.Results: Median follow-up was 55.6 months (range 7.6-141.9 months). The 3- and 5-year probability of biochemical relapse-free survival were 87% and 81%, respectively. In univariate analysis, more advanced T stages, preoperative PSA values ≥10 ng/mL, and RT doses <70 Gy were significant factors for biochemical relapse. Pre-RT PSA values >0.2 ng/mL were significant for distant metastases. In multivariate analysis, risk factors for biochemical relapse were higher preoperative and pre-RT PSA values, hormone therapy for under 402 days and RT doses of <70 Gy. Higher pre-RT PSA values were the only independent predictor of distant metastases. Acute genitourinary (GU) and gastrointestinal (GI) toxicities occurred in 72 (39.6%) and 91 (50%) patients, respectively. There were 2 cases of Grade III GI toxicity but no cases of Grade IV. Late GU and GI toxicities occurred in 28 (15.4%) and 14 (7.7%) patients, respectively: 11 cases of Grade III toxicity: 1 GI (anal stenosis) and 10 GU, all urethral strictures requiring endoscopic urethrotomy.Conclusions: Postoperative high-dose conformal RT in patients with high-risk features was associated with a low risk of biochemical relapse as well as minimal morbidity.

The Use of Photon Beams of a Flattening Filter-free Linear Accelerator for Hypofractionated Volumetric Modulated Arc Therapy in Localized Prostate Cancer - Corrected Proof

2012-05-08

Purpose: To evaluate the potential usage of flattening filter-free (FFF) photon beams in the treatment of prostate cancer.Methods and Materials: Volumetric-modulated arc therapy (VMAT) treatment planning was performed for 7 patients using TrueBeam® linear accelerator and photon beams with (X6, X10) and without (X6FFF, X10FFF) flattening filter. Prescribed dose was 19 × 3 Gy = 57 Gy. One or two 360° arcs with dose rate of 600 MU/min for flattened beams, and 1,200 MU/min for FFF beams were used.Results: No difference was detected between the four beams in PTV coverage, conformity, and homogeneity. Mean body dose and body volume receiving 50% of the prescribed dose decreased with increasing mean energy (r2 = 0.8275, p < 0.01). X6FFF delivered 3.6% more dose compared with the X6 (p < 0.01). X10FFF delivered 3.0% (p < 0.01), and the X10 5.8% (p < 0.01) less mean body dose compared with X6. There was a significant increase in the mean dose to the rectum for the X10 compared with X6 (2.6%, p < 0.01). Mean dose to the bladder increased by 1.3% for X6FFF and decreased by 2.3% for X10FFF. Using a single arc and FFF, treatment time was reduced by 35% (2 SD = 10%).Conclusion: FFF beams resulted in dose distributions similar to flattened beams. X10FFF beam provided the best solution, sparing rectum and bladder and minimizing whole-body dose. FFF beams lead to a time efficient treatment delivery, particularly when combined with hypofractionated VMAT.

Positron Emission Tomography for Assessing Local Failure After Stereotactic Body Radiotherapy for Non-Small-Cell Lung Cancer - Corrected Proof

2012-05-08

Purpose: We analyzed whether positron emission tomography (PET)/computed tomography standardized uptake values (SUVs) after stereotactic body radiotherapy (SBRT) could predict local recurrence (LR) in non-small-cell lung cancer (NSCLC).Methods and Materials: This study comprised 128 patients with Stage I (n = 68) or isolated recurrent/secondary parenchymal (n = 60) NSCLC treated with image-guided SBRT to 50 Gy over 4 consecutive days; prior radiotherapy was allowed. PET/computed tomography scans were obtained before therapy and at 1 to 6 months after therapy, as well as subsequently as clinically indicated. Continuous variables were analyzed with Kruskal-Wallis tests and categorical variables with Pearson chi-square or Fisher exact tests. Actuarial local failure rates were calculated with the Kaplan-Meier method.Results: At a median follow-up of 31 months (range, 6–71 months), the actuarial 1-, 2-, and 3-year local control rates were 100%, 98.5%, and 98.5%, respectively, in the Stage I group and 95.8%, 87.6%, and 85.8%, respectively, in the recurrent group. The cumulative rates of regional nodal recurrence and distant metastasis were 8.8% (6 of 68) and 14.7% (10 of 68), respectively, for the Stage I group and 11.7% (7 of 60) and 16.7% (10 of 60), respectively, for the recurrent group. Univariate analysis showed that SUVs obtained 12.1 to 24 months after treatment for the Stage I group (p = 0.007) and 6.1 to 12 months and 12.1 to 24 months after treatment for the recurrent group were associated with LR (p < 0.001 for both). Of the 128 patients, 17 (13.3%) had ipsilateral consolidation after SBRT but no elevated metabolic activity on PET; none had LR. The cutoff maximum SUV of 5 was found to have 100% sensitivity, 91% specificity, a 50% positive predictive value, and a 100% negative predictive value for predicting LR.Conclusions: PET was helpful for distinguishing SBRT-induced consolidation from LR. SUVs obtained more than 6 months after SBRT for NSCLC were associated with local failure. A maximum SUV greater than 5, especially at more than 6 months after SBRT, should prompt biopsy to rule out LR.

Esophageal Toxicity From High-Dose, Single-Fraction Paraspinal Stereotactic Radiosurgery - Corrected Proof

Brett W. Cox, Andrew Jackson, Margie Hunt, Mark Bilsky, Yoshiya Yamada — 2012-05-08

Purpose: To report the esophageal toxicity from single-fraction paraspinal stereotactic radiosurgery (SRS) and identify dosimetric and clinical risk factors for toxicity.Methods and Materials: A total of 204 spinal metastases abutting the esophagus (182 patients) were treated with high-dose single-fraction SRS during 2003-2010. Toxicity was scored using the National Cancer Institute Common Toxicity Criteria for Adverse Events, version 4.0. Dose-volume histograms were combined to generate a comprehensive atlas of complication incidence that identifies risk factors for toxicity. Correlation of dose-volume factors with esophageal toxicity was assessed using Fisher’s exact test and logistic regression. Clinical factors were correlated with toxicity.Results: The median dose to the planning treatment volume was 24 Gy. Median follow-up was 12 months (range, 3-81). There were 31 (15%) acute and 24 (12%) late esophageal toxicities. The rate of grade ≥3 acute or late toxicity was 6.8% (14 patients). Fisher’s exact test resulted in significant median splits for grade ≥3 toxicity at V12 = 3.78 cm3 (relative risk [RR] 3.7, P=.05), V15 = 1.87 cm3 (RR 13, P=.0013), V20 = 0.11 cm3 (RR 6, P=0.01), and V22 = 0.0 cm3 (RR 13, P=.0013). The median split for D2.5 cm3 (14.02 Gy) was also a significant predictor of toxicity (RR 6; P=.01). A highly significant logistic regression model was generated on the basis of D2.5 cm3. One hundred percent (n = 7) of grade ≥4 toxicities were associated with radiation recall reactions after doxorubicin or gemcitabine chemotherapy or iatrogenic manipulation of the irradiated esophagus.Conclusions: High-dose, single-fraction paraspinal SRS has a low rate of grade ≥3 esophageal toxicity. Severe esophageal toxicity is minimized with careful attention to esophageal doses during treatment planning. Iatrogenic manipulation of the irradiated esophagus and systemic agents classically associated with radiation recall reactions are associated with development of grade ≥4 toxicity.

Long-Term Results Following Postoperative Radiotherapy for Soft Tissue Sarcomas of the Extremity - Corrected Proof

2012-05-07

Purpose: To review long-term outcomes following postoperative radiotherapy (RT) for extremity soft tissue sarcoma (STS) and identify variables affecting the therapeutic ratio.Methods and Materials: Between 1970 and 2008, 173 patients with localized extremity STS were treated with postoperative radiation. No patients received prior irradiation. Sixteen percent of tumors had recurred after initial surgery alone; 89% of tumors were high grade. The median patient age was 57 years (range, 18-86 years). Sixty-one percent underwent >1 surgery before RT in an attempt to achieve wide negative margins. Final margin status was negative in 70% and marginal or microscopically positive in 30%. The median time between final surgery and start of RT was 40 days. The median RT dose was 65 Gy (range, 49-74 Gy). The median follow-up for all patients was 10.4 years and 13.2 years among survivors.Results: At 10 years, local control (LC), cause-specific survival (CSS), and overall survival (OS) rates were 87%, 80%, and 70%, respectively, with 89% of local failures occurring within 3 years after treatment. On multivariate analysis, age >55 years (82% vs 93%, P 55 years and local recurrence were associated with inferior CSS and OS on multivariate analysis. Twelve percent of patients experienced grade 3+ toxicity; 12 of these occurred in patients with tumors of the proximal lower extremity, with the most common toxicity of pathologic fracture occurring in 6.3%.Conclusions: This large single-institution series confirms that postoperative RT for STS of the extremities provides good long-term disease control with acceptable toxicity. Our experience supports recurrent presentation and older age as adverse prognostic factors for LC.

Phase II Study of Accelerated High-Dose Radiotherapy With Concurrent Chemotherapy for Patients With Limited Small-Cell Lung Cancer: Radiation Therapy Oncology Group Protocol 0239 - Corrected Proof

2012-05-07

Purpose: To investigate whether high-dose thoracic radiation given twice daily during cisplatin-etoposide chemotherapy for limited small-cell lung cancer (LSCLC) improves survival, acute esophagitis, and local control rates relative to findings from Intergroup trial 0096 (47%, 27%, and 64%).Patients and Methods: Patients were accrued over a 3-year period from 22 US and Canadian institutions. Patients with LSCLC and good performance status were given thoracic radiation to 61.2 Gy over 5 weeks (daily 1.8-Gy fractions on days 1-22, then twice-daily 1.8-Gy fractions on days 23-33). Cisplatin (60 mg/m2 IV) was given on day 1 and etoposide (120 mg/m2 IV) on days 1-3 and days 22-24, followed by 2 cycles of cisplatin plus etoposide alone. Patients who achieved complete response were offered prophylactic cranial irradiation. Endpoints included overall and progression-free survival; severe esophagitis (Common Toxicity Criteria v 2.0) and treatment-related fatalities; response (Response Evaluation Criteria in Solid Tumors); and local control.Results: Seventy-two patients were accrued from June 2003 through May 2006; 71 were evaluable (median age 63 years; 52% female; 58% Zubrod 0). Median survival time was 19 months; at 2 years, the overall survival rate was 36.6% (95% confidence interval [CI] 25.6%-47.7%), and progression-free survival 19.7% (95% CI 11.4%-29.6%). Thirteen patients (18%) experienced severe acute esophagitis, and 2 (3%) died of treatment-related causes; 41% achieved complete response, 39% partial response, 10% stable disease, and 6% progressive disease. The local control rate was 73%. Forty-three patients (61%) received prophylactic cranial irradiation.Conclusions: The overall survival rate did not reach the projected goal; however, rates of esophagitis were lower, and local control higher, than projected. This treatment strategy is now one of three arms of a prospective trial of chemoradiation for LSCLC (Radiation Therapy Oncology Group 0538/Cancer and Leukemia Group B 30610).

Impact of Postmastectomy Radiation on Locoregional Recurrence in Breast Cancer Patients With 1-3 Positive Lymph Nodes Treated With Modern Systemic Therapy - Corrected Proof

2012-05-07

Purpose: Postmastectomy radiation therapy (PMRT) remains controversial for patients with 1-3 positive lymph nodes (LN+).Methods and Materials: We conducted a retrospective review of all 369 breast cancer patients with 1-3 LN+ who underwent mastectomy without neoadjuvant systemic therapy between 2000 and 2007 at Cleveland Clinic.Results: We identified 271 patients with 1-3 LN+ who did not receive PMRT and 98 who did receive PMRT. The median follow-up time was 5.2 years, and the median number of LN dissected was 11. Of those not treated with PMRT, 79% received adjuvant chemotherapy (of whom 70% received a taxane), 79% received hormonal therapy, and 5% had no systemic therapy. Of the Her2/neu amplified tumors, 42% received trastuzumab. The 5-year rate of locoregional recurrence (LRR) was 8.9% without PMRT vs 0% with PMRT (P=.004). For patients who did not receive PMRT, univariate analysis showed 6 risk factors significantly (P 25% (HR 2.7), extracapsular extension (ECE) (HR 3.7), and Bloom-Richardson grade III (HR 3.1). The 5-year LRR rate was 3.4% (95% confidence interval [CI], 0.1%-6.8%] for patients with 0-1 risk factor vs 14.6% [95% CI, 8.4%-20.9%] for patients with ≥2 risk factors (P=.0006), respectively. On multivariate analysis, ECE (HR 4.3, P=.0006) and grade III (HR 3.6, P=.004) remained significant risk factors for LRR. The 5-year LRR was 4.1% in patients with neither grade III nor ECE, 8.1% with either grade III or ECE, and 50.4% in patients with both grade III and ECE (P<.0001); the corresponding 5-year distant metastasis-free survival rates were 91.8%, 85.4%, and 59.1% (P=.0004), respectively.Conclusions: PMRT offers excellent control for patients with 1-3 LN+, with no locoregional failures to date. Patients with 1-3 LN+ who have grade III disease and/or ECE should be strongly considered for PMRT.

Positron Emission Tomography (PET) Evaluation After Initial Chemotherapy and Radiation Therapy Predicts Local Control in Rhabdomyosarcoma - Corrected Proof

2012-05-07

Purpose: 18-fluorodeoxyglucose positron emission tomography (PET) is already an integral part of staging in rhabdomyosarcoma. We investigated whether primary-site treatment response characterized by serial PET imaging at specific time points can be correlated with local control.Patients and Methods: We retrospectively examined 94 patients with rhabdomyosarcoma who received initial chemotherapy 15 weeks (median) before radiotherapy and underwent baseline, preradiation, and postradiation PET. Baseline PET standardized uptake values (SUVmax) and the presence or absence of abnormal uptake (termed PET-positive or PET-negative) both before and after radiation were examined for the primary site. Local relapse-free survival (LRFS) was calculated according to baseline SUVmax, PET-positive status, and PET-negative status by the Kaplan-Meier method, and comparisons were tested with the log-rank test.Results: The median patient age was 11 years. With 3-year median follow-up, LRFS was improved among postradiation PET-negative vs PET-positive patients: 94% vs 75%, P=.02. By contrast, on baseline PET, LRFS was not significantly different for primary-site SUVmax ≤7 vs >7 (median), although the findings suggested a trend toward improved LRFS: 96% for SUVmax ≤7 vs 79% for SUVmax >7, P=.08. Preradiation PET also suggested a statistically insignificant trend toward improved LRFS for PET-negative (97%) vs PET-positive (81%) patients (P=.06).Conclusion: Negative postradiation PET predicted improved LRFS. Notably, 77% of patients with persistent postradiation uptake did not experience local failure, suggesting that these patients could be closely followed up rather than immediately referred for intervention. Negative baseline and preradiation PET findings suggested statistically insignificant trends toward improved LRFS. Additional study may further understanding of relationships between PET findings at these time points and outcome in rhabdomyosarcoma.

Fractionated Stereotactic Radiotherapy of Vestibular Schwannomas Accelerates Hearing Loss - Corrected Proof

2012-05-07

Objective: To evaluate long-term tumor control and hearing preservation rates in patients with vestibular schwannoma treated with fractionated stereotactic radiotherapy (FSRT), comparing hearing preservation rates to an untreated control group. The relationship between radiation dose to the cochlea and hearing preservation was also investigated.Materials and Methods: Forty-two patients receiving FSRT between 1997 and 2008 with a minimum follow-up of 2 years were included. All patients received 54 Gy in 27-30 fractions during 5.5-6.0 weeks. Clinical and audiometry data were collected prospectively. From a “wait-and-scan” group, 409 patients were selected as control subjects, matched by initial audiometric parameters. Radiation dose to the cochlea was measured using the original treatment plan and then related to changes in acoustic parameters.Results: Actuarial 2-, 4-, and 10-year tumor control rates were 100%, 91.5%, and 85.0%, respectively. Twenty-one patients had serviceable hearing before FSRT, 8 of whom (38%) retained serviceable hearing at 2 years after FSRT. No patients retained serviceable hearing after 10 years. At 2 years, hearing preservation rates in the control group were 1.8 times higher compared with the group receiving FSRT (P=.007). Radiation dose to the cochlea was significantly correlated to deterioration of the speech reception threshold (P=.03) but not to discrimination loss.Conclusion: FSRT accelerates the naturally occurring hearing loss in patients with vestibular schwannoma. Our findings, using fractionation of radiotherapy, parallel results using single-dose radiation. The radiation dose to the cochlea is correlated to hearing loss measured as the speech reception threshold.

How Radiation Oncologists Would Disclose Errors: Results of a Survey of Radiation Oncologists and Trainees - Corrected Proof

Suzanne B. Evans, James B. Yu, Anees Chagpar — 2012-05-07

Purpose: To analyze error disclosure attitudes of radiation oncologists and to correlate error disclosure beliefs with survey-assessed disclosure behavior.Methods and Materials: With institutional review board exemption, an anonymous online survey was devised. An email invitation was sent to radiation oncologists (American Society for Radiation Oncology [ASTRO] gold medal winners, program directors and chair persons of academic institutions, and former ASTRO lecturers) and residents. A disclosure score was calculated based on the number or full, partial, or no disclosure responses chosen to the vignette-based questions, and correlation was attempted with attitudes toward error disclosure.Results: The survey received 176 responses: 94.8% of respondents considered themselves more likely to disclose in the setting of a serious medical error; 72.7% of respondents did not feel it mattered who was responsible for the error in deciding to disclose, and 3.9% felt more likely to disclose if someone else was responsible; 38.0% of respondents felt that disclosure increased the likelihood of a lawsuit, and 32.4% felt disclosure decreased the likelihood of lawsuit; 71.6% of respondents felt near misses should not be disclosed; 51.7% thought that minor errors should not be disclosed; 64.7% viewed disclosure as an opportunity for forgiveness from the patient; and 44.6% considered the patient's level of confidence in them to be a factor in disclosure. For a scenario that could be considerable, a non-harmful error, 78.9% of respondents would not contact the family. Respondents with high disclosure scores were more likely to feel that disclosure was an opportunity for forgiveness (P=.003) and to have never seen major medical errors (P=.004).Conclusions: The surveyed radiation oncologists chose to respond with full disclosure at a high rate, although ideal disclosure practices were not uniformly adhered to beyond the initial decision to disclose the occurrence of the error.

Success Breeds Success: Authorship Distribution in the Red Journal, 1975-2011 - Corrected Proof

Emma Holliday, Clifton David Fuller, Lynn D. Wilson, Charles R. Thomas — 2012-05-07

Purpose: Publication analysis has value in evaluating the mechanics of academic efforts in specific scientific communities. The specific aim of this study was to evaluate whether established bibliometric patterns seen in other academic fields were likewise observed in radiation oncology publication parameters.Methods and Materials: We used a commercial bibliographic database to analyze all publications in Red Journal, or International Journal of Radiation Oncology Biology Physics (IJROBP), the New England Journal of Medicine (NEJM), the Journal of Clinical Oncology (JCO), and Radiology (Rad) between January 1, 1975 and May 18, 2011. Power-law (Lotka's law or 1/n2) conformance was assessed. Curve fit analysis was then performed.Results: In all 4 journals, a total of 219,476 authors were responsible for 62,232 articles. Of those, 79,810 authors published 13,772 articles in IJROBP, with 79,446/16,707 authors/articles in NEJM, 106,984/11,920 authors/articles in JCO and 90,325/19,745 authors/articles in Rad. The mean ± standard deviation of authors per publication was 5.74 ± 4.61 overall. There were 5.8 ± 3.53, 4.8 ± 5.7, 8.9 ± 3.53, and 4.6 ± 2.8 authors per article in IJROBP, NEJM, JCO, and Rad, respectively (P<.001). The number of authors publishing n articles was 1/n2.02 of those publishing 1 article in IJROBP, 1/n2.52 in NEJM, 1/n1.97 in JCO, and 1/n2.16 in Rad.Conclusions: Bibliometric analysis shows that authorship distributions in IJROBP approximate those of the scientific literature in comparable scientific journals. Our results suggest that the majority of publications in the field of radiation oncology are produced by a small but highly productive group of authors.

Evaluation of Tumor Shape Variability in Head-and-Neck Cancer Patients Over the Course of Radiation Therapy Using Implanted Gold Markers - Corrected Proof

2012-05-07

Purpose: This study quantifies tumor shape variability in head-and-neck cancer patients during radiation therapy using implanted markers.Methods and Materials: Twenty-seven patients with oropharyngeal tumors treated with (chemo)radiation were included. Helical gold markers (0.35 × 2 mm, 3-10/patient, average 6) were implanted around the tumor. Markers were identified on planning computed tomography (CT) and daily cone beam CT (CBCT). After bony anatomy registration, the daily vector length on CBCT in reference to the planning CT and daily marker movement perpendicular to the gross tumor volume (GTV) surface at planning CT (dnormal) of each marker were analyzed. Time trends were assessed with linear regression of the markers. In 2 patients, 2 markers were implanted in normal tissue to evaluate migration by measuring intermarker distances.Results: Marker implantation was feasible without complications. Three-dimensional vectors (4827 measurements, mean 0.23 cm, interquartile ratio 0.24 cm) were highest in base of tongue sublocalization (P<.001) and bulky tumors (vectors exceeded 0.5 cm in 5.7% [0-20 mL], 12.0% [21-40 mL], and 21.7% [≥41 mL], respectively [P<.001] of measurements). The measured inward time trend in 11/27 patients correlated with the visual observed marker pattern. In patients with an outward trend (5/27) or no trend (11/27), visual observation showed predominantly an inhomogeneous pattern. Remarkably, in 6 patients, outward marker movement was observed in the posterior pharyngeal wall. The difference in distance between normal tissue markers (1 SD) was 0.05-0.06 cm without time trend, indicating that implanted markers did not migrate.Conclusions: During head-and-neck radiation therapy, normal tissue markers remained stable. Changes in position of tumor markers depended on sublocalization and tumor volume. Large differences in marker patterns between patients as well as within patients were observed. Based on our study, the cranial and caudal border in the posterior pharyngeal wall are at highest risk to be covered insufficiently. Furthermore, implanted markers could help identify patients with an actual shrinkage of the GTV who might benefit from mid-radiation therapy redelineation to reduce toxicity.

Cosmetic Outcome and Seroma Formation After Breast-Conserving Surgery With Intraoperative Radiation Therapy Boost for Early Breast Cancer - Corrected Proof

Sashendra Senthi, Emma Link, Boon H. Chua — 2012-05-07

Purpose: To evaluate cosmetic outcome and its association with breast wound seroma after breast-conserving surgery (BCS) with targeted intraoperative radiation therapy (tIORT) boost for early breast cancer.Methods and Materials: An analysis of a single-arm prospective study of 55 patients with early breast cancer treated with BCS and tIORT boost followed by conventional whole breast radiation therapy (WBRT) between August 2003 and January 2006 was performed. A seroma was defined as a fluid collection at the primary tumor resection site identified clinically or radiologically. Cosmetic assessments using the European Organization for Research and Treatment of Cancer rating system were performed at baseline before BCS and 30 months after WBRT was completed.Results: Twenty-eight patients (51%) developed a seroma, with 18 patients (33%) requiring at least 1 aspiration. Tumor location was significantly associated with seroma formation (P=.001). Ten of 11 patients with an upper inner quadrant tumor developed a seroma. Excellent or good overall cosmetic outcome at 30 months was observed in 34 patients (62%, 95% confidence interval 53%-80%). Seroma formation was not associated with the overall cosmetic result (P=.54).Conclusion: BCS with tIORT boost followed by WBRT was associated with an acceptable cosmetic outcome. Seroma formation was not significantly associated with an adverse cosmetic outcome.

The Abscopal Effect Associated With a Systemic Anti-melanoma Immune Response - Corrected Proof

Emily F. Stamell, Jedd D. Wolchok, Sacha Gnjatic, Nancy Y. Lee, Isaac Brownell — 2012-05-07

The clearance of nonirradiated tumors after localized radiation therapy is known as the abscopal effect. Activation of an antitumor immune response has been proposed as a mechanism for the abscopal effect. Here we report a patient with metastatic melanoma who received palliative radiation to his primary tumor with subsequent clearance of all his nonirradiated in-transit metastases. Anti-MAGEA3 antibodies were found upon serological testing, demonstrating an association between the abscopal effect and a systemic antitumor immune response. A brain recurrence was then treated with a combination of stereotactic radiosurgery and immunotherapy with ipilimumab. The patient experienced a complete remission that included resolution of nodal metastases, with a concomitant increase in MAGEA3 titers and a new response to the cancer antigen PASD1. This case supports the immune hypothesis for the abscopal effect, and illustrates the potential of combining radiotherapy and immunotherapy in the treatment of melanoma.

Cone Beam Computed Tomography Image Guidance System for a Dedicated Intracranial Radiosurgery Treatment Unit - Corrected Proof

2012-05-07

Purpose: Image guidance has improved the precision of fractionated radiation treatment delivery on linear accelerators. Precise radiation delivery is particularly critical when high doses are delivered to complex shapes with steep dose gradients near critical structures, as is the case for intracranial radiosurgery. To reduce potential geometric uncertainties, a cone beam computed tomography (CT) image guidance system was developed in-house to generate high-resolution images of the head at the time of treatment, using a dedicated radiosurgery unit. The performance and initial clinical use of this imaging system are described.Methods and Materials: A kilovoltage cone beam CT system was integrated with a Leksell Gamma Knife Perfexion radiosurgery unit. The X-ray tube and flat-panel detector are mounted on a translational arm, which is parked above the treatment unit when not in use. Upon descent, a rotational axis provides 210° of rotation for cone beam CT scans. Mechanical integrity of the system was evaluated over a 6-month period. Subsequent clinical commissioning included end-to-end testing of targeting performance and subjective image quality performance in phantoms. The system has been used to image 2 patients, 1 of whom received single-fraction radiosurgery and 1 who received 3 fractions, using a relocatable head frame.Results: Images of phantoms demonstrated soft tissue contrast visibility and submillimeter spatial resolution. A contrast difference of 35 HU was easily detected at a calibration dose of 1.2 cGy (center of head phantom). The shape of the mechanical flex vs scan angle was highly reproducible and exhibited <0.2 mm peak-to-peak variation. With a 0.5-mm voxel pitch, the maximum targeting error was 0.4 mm. Images of 2 patients were analyzed offline and submillimeter agreement was confirmed with conventional frame.Conclusions: A cone beam CT image guidance system was successfully adapted to a radiosurgery unit. The system is capable of producing high-resolution images of bone and soft tissue. The system is in clinical use and provides excellent image guidance without invasive frames.

Using Generalized Equivalent Uniform Dose Atlases to Combine and Analyze Prospective Dosimetric and Radiation Pneumonitis Data From 2 Non-Small Cell Lung Cancer Dose Escalation Protocols - Corrected Proof

2012-05-07

Purpose: To demonstrate the use of generalized equivalent uniform dose (gEUD) atlas for data pooling in radiation pneumonitis (RP) modeling, to determine the dependence of RP on gEUD, to study the consistency between data sets, and to verify the increased statistical power of the combination.Methods and Materials: Patients enrolled in prospective phase I/II dose escalation studies of radiation therapy of non-small cell lung cancer at Memorial Sloan-Kettering Cancer Center (MSKCC) (78 pts) and the Netherlands Cancer Institute (NKI) (86 pts) were included; 10 (13%) and 14 (17%) experienced RP requiring steroids (RPS) within 6 months after treatment. gEUD was calculated from dose-volume histograms. Atlases for each data set were created using 1-Gy steps from exact gEUDs and RPS data. The Lyman-Kutcher-Burman model was fit to the atlas and exact gEUD data. Heterogeneity and inconsistency statistics for the fitted parameters were computed. gEUD maps of the probability of RPS rate ≥20% were plotted.Results: The 2 data sets were homogeneous and consistent. The best fit values of the volume effect parameter a were small, with upper 95% confidence limit around 1.0 in the joint data. The likelihood profiles around the best fit a values were flat in all cases, making determination of the best fit a weak. All confidence intervals (CIs) were narrower in the joint than in the individual data sets. The minimum P value for correlations of gEUD with RPS in the joint data was .002, compared with P=.01 and .05 for MSKCC and NKI data sets, respectively. gEUD maps showed that at small a, RPS risk increases with gEUD.Conclusions: The atlas can be used to combine gEUD and RPS information from different institutions and model gEUD dependence of RPS. RPS has a large volume effect with the mean dose model barely included in the 95% CI. Data pooling increased statistical power.

Quantifying the Impact of Immediate Reconstruction in Postmastectomy Radiation: A Large, Dose-Volume Histogram-Based Analysis - Corrected Proof

2012-05-07

Purpose: To assess the impact of immediate breast reconstruction on postmastectomy radiation (PMRT) using dose-volume histogram (DVH) data.Methods and Materials: Two hundred forty-seven women underwent PMRT at our center, 196 with implant reconstruction and 51 without reconstruction. Patients with reconstruction were treated with tangential photons, and patients without reconstruction were treated with en-face electron fields and customized bolus. Twenty percent of patients received internal mammary node (IMN) treatment. The DVH data were compared between groups. Ipsilateral lung parameters included V20 (% volume receiving 20 Gy), V40 (% volume receiving 40 Gy), mean dose, and maximum dose. Heart parameters included V25 (% volume receiving 25 Gy), mean dose, and maximum dose. IMN coverage was assessed when applicable. Chest wall coverage was assessed in patients with reconstruction. Propensity-matched analysis adjusted for potential confounders of laterality and IMN treatment.Results: Reconstruction was associated with lower lung V20, mean dose, and maximum dose compared with no reconstruction (all P 98%). IMN coverage was superior in patients with reconstruction (D95 >92.0 vs 75.7%, P .05). Among IMN-treated patients, only lower lung V20 in those without reconstruction persisted (P=.022), and mean and maximum heart doses were higher than in patients without reconstruction (P=.006, P=.015, respectively).Conclusions: Implant reconstruction does not compromise the technical quality of PMRT when the IMNs are untreated. Treatment technique, not reconstruction, is the primary determinant of target coverage and normal tissue doses.

Acute Esophagus Toxicity in Lung Cancer Patients After Intensity Modulated Radiation Therapy and Concurrent Chemotherapy - Corrected Proof

2012-05-07

Purpose: The purpose of this study was to investigate the dose-effect relation between acute esophageal toxicity (AET) and the dose-volume parameters of the esophagus after intensity modulated radiation therapy (IMRT) and concurrent chemotherapy for patients with non-small cell lung cancer (NSCLC).Patients and Methods: One hundred thirty-nine patients with inoperable NSCLC treated with IMRT and concurrent chemotherapy were prospectively analyzed. The fractionation scheme was 66 Gy in 24 fractions. All patients received concurrently a daily dose of cisplatin (6 mg/m²). Maximum AET was scored according to Common Toxicity Criteria 3.0. Dose-volume parameters V5 to V70, Dmean and Dmax of the esophagus were calculated. A logistic regression analysis was performed to analyze the dose-effect relation between these parameters and grade ≥2 and grade ≥3 AET. The outcome was compared with the clinically used esophagus V35 prediction model for grade ≥2 after radical 3-dimensional conformal radiation therapy (3DCRT) treatment.Results: In our patient group, 9% did not experience AET, and 31% experienced grade 1 AET, 38% grade 2 AET, and 22% grade 3 AET. The incidence of grade 2 and grade 3 AET was not different from that in patients treated with CCRT using 3DCRT. The V50 turned out to be the most significant dosimetric predictor for grade ≥3 AET (P=.012). The derived V50 model was shown to predict grade ≥2 AET significantly better than the clinical V35 model (P<.001).Conclusions: For NSCLC patients treated with IMRT and concurrent chemotherapy, the V50 was identified as most accurate predictor of grade ≥3 AET. There was no difference in the incidence of grade ≥2 AET between 3DCRT and IMRT in patients treated with concurrent chemoradiation therapy.

Intrafraction Verification of Gated RapidArc by Using Beam-Level Kilovoltage X-Ray Images - Corrected Proof

2012-05-03

Purpose: To verify the geometric accuracy of gated RapidArc treatment using kV images acquired during dose delivery.Methods and Materials: Twenty patients were treated using the gated RapidArc technique with a Varian TrueBeam STx linear accelerator. One to 7 metallic fiducial markers were implanted inside or near the tumor target before treatment simulation. For patient setup and treatment verification purposes, the internal target volume (ITV) was created, corresponding to each implanted marker. The gating signal was generated from the Real-time Position Management (RPM) system. At the beginning of each fraction, individualized respiratory gating amplitude thresholds were set based on fluoroscopic image guidance. During the treatment, we acquired kV images immediately before MV beam-on at every breathing cycle, using the on-board imaging system. After the treatment, all implanted markers were detected, and their 3-dimensional (3D) positions in the patient were estimated using software developed in-house. The distance from the marker to the corresponding ITV was calculated for each patient by averaging over all markers and all fractions.Results: The average 3D distance between the markers and their ITVs was 0.8 ± 0.5 mm (range, 0-1.7 mm) and was 2.1 ± 1.2 mm at the 95th percentile (range, 0-3.8 mm). On average, a left-right margin of 0.6 mm, an anterior-posterior margin of 0.8 mm, and a superior-inferior margin of 1.5 mm is required to account for 95% of the intrafraction uncertainty in RPM-based RapidArc gating.Conclusion: To our knowledge, this is the first clinical report of intrafraction verification of respiration-gated RapidArc treatment in stereotactic ablative radiation therapy. For some patients, the markers deviated significantly from the ITV by more than 2 mm at the beginning of the MV beam-on. This emphasizes the need for gating techniques with beam-on/-off controlled directly by the actual position of the tumor target instead of external surrogates such as RPM.

The Dosimetric Impact of Prostate Rotations During Electromagnetically Guided External-Beam Radiation Therapy - Corrected Proof

2012-05-03

Purpose: To study the impact of daily rotations and translations of the prostate on dosimetric coverage during radiation therapy (RT).Methods and Materials: Real-time tracking data for 26 patients were obtained during RT. Intensity modulated radiation therapy plans meeting RTOG 0126 dosimetric criteria were created with 0-, 2-, 3-, and 5-mm planning target volume (PTV) margins. Daily translations and rotations were used to reconstruct prostate delivered dose from the planned dose. D95 and V79 were computed from the delivered dose to evaluate target coverage and the adequacy of PTV margins. Prostate equivalent rotation is a new metric introduced in this study to quantify prostate rotations by accounting for prostate shape and length of rotational lever arm.Results: Large variations in prostate delivered dose were seen among patients. Adequate target coverage was met in 39%, 65%, and 84% of the patients for plans with 2-, 3-, and 5-mm PTV margins, respectively. Although no correlations between prostate delivered dose and daily rotations were seen, the data showed a clear correlation with prostate equivalent rotation.Conclusions: Prostate rotations during RT could cause significant underdosing even if daily translations were managed. These rotations should be managed with rotational tolerances based on prostate equivalent rotations.