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Publications in this journal

• Different Dose Escalation Protocols for Esophageal Primaries: Like Comparing Apples and Oranges? In regard to Welsh et al (Int J Radiat Oncol Biol Phys 2012;82:468-474).

  Authors: Abhishek Puri

  International journal of radiation oncology, biology, physics. 83(2):480.

• In regard to "Indications for Pelvic Nodal Treatment in Prostate Cancer Should Change. Validation of the Roach Formula in a Large Extended Nodal Dissection Series." (Int J Radiat Oncol Biol Phys 2012;83:624-629).

  Authors: James B Yu

  International journal of radiation oncology, biology, physics. 83(2):481.

• Need for Neck Dissection: A Premature Epitaph for "obsolete paradigm"? In regard to Clavel et al (Int J Radiat Oncol Biol Phys 2012;82:e567-e573).

  Authors: Abhishek Puri

  International journal of radiation oncology, biology, physics. 83(2):483-4.

• Esophageal Delineation: In regard to Kong et al "Consideration of Dose Limits for Organs at Risk of Thoracic Radiotherapy: Atlas for Lung, Proximal Bronchial Tree, Esophagus, Spinal Cord, Ribs, and Brachial Plexus" (Int J Radiat Oncol Biol Phys 2011;81:1442-1457).

  Authors: Timothy Zagar, Lawrence Marks

  International journal of radiation oncology, biology, physics. 83(2):484-5.

• Role of Postmastectomy Radiation After Neoadjuvant Chemotherapy in Stage II-III Breast Cancer.

  Authors: Barbara L Fowble, John P Einck, Danny N Kim, Susan McCloskey, Jyoti Mayadev, Catheryn Yashar, Steven L Chen, E Shelley Hwang

  International journal of radiation oncology, biology, physics. 83(2):494-503.

  To identify a cohort of women treated with neoadjuvant chemotherapy and mastectomy for whom postmastectomy radiation therapy (PMRT) may be omitted according to the projected risk of local-regionalTo identify a cohort of women treated with neoadjuvant chemotherapy and mastectomy for whom postmastectomy radiation therapy (PMRT) may be omitted according to the projected risk of local-regional failure (LRF). Seven breast cancer physicians from the University of California cancer centers created 14 hypothetical clinical case scenarios, identified, reviewed, and abstracted the available literature (MEDLINE and Cochrane databases), and formulated evidence tables with endpoints of LRF, disease-free survival, and overall survival. Using the American College of Radiology appropriateness criteria methodology, appropriateness ratings for postmastectomy radiation were assigned for each scenario. Finally, an overall summary risk assessment table was developed. Of 24 sources identified, 23 were retrospective studies from single institutions. Consensus on the appropriateness rating, defined as 80% agreement in a category, was achieved for 86% of the cases. Distinct LRF risk categories emerged. Clinical stage II (T1-2N0-1) patients, aged >40 years, estrogen receptor-positive subtype, with pathologic complete response or 0-3 positive nodes without lymphovascular invasion or extracapsular extension, were identified as having ≤10% risk of LRF without radiation. Limited data support stage IIIA patients with pathologic complete response as being low risk. In the absence of randomized trial results, existing data can be used to guide the use of PMRT in the neoadjuvant chemotherapy setting. Using available studies to inform appropriateness ratings for clinical scenarios, we found a high concordance of treatment recommendations for PMRT and were able to identify a cohort of women with a low risk of LRF without radiation. These low-risk patients will form the basis for future planned studies within the University of California Athena Breast Health Network.

• Correlation in rectal cancer between clinical tumor response after neoadjuvant radiotherapy and sphincter or organ preservation: 10-year results of the lyon R 96-02 randomized trial.

  Authors: Cécile Ortholan, Pascale Romestaing, Olivier Chapet, Jean Pierre Gerard

  International journal of radiation oncology, biology, physics. 83(2):e165-71.

  To investigate, in rectal cancer, the benefit of a neoadjuvant radiation dose escalation with endocavitary contact radiotherapy (CXRT) in addition to external beam radiotherapy (EBRT). This articleTo investigate, in rectal cancer, the benefit of a neoadjuvant radiation dose escalation with endocavitary contact radiotherapy (CXRT) in addition to external beam radiotherapy (EBRT). This article provides an update of the Lyon R96-02 Phase III trial. A total of 88 patients with T2 to T3 carcinoma of the lower rectum were randomly assigned to neoadjuvant EBRT 39 Gy in 13 fractions (43 patients) vs. the same EBRT with CXRT boost, 85 Gy in three fractions (45 patients). Median follow-up was 132 months. The 10-year cumulated rate of permanent colostomy (CRPC) was 63% in the EBRT group vs. 29% in the EBRT+CXRT group (p < 0.001). The 10-year rate of local recurrence was 15% vs. 10% (p = 0.69); 10-year disease-free survival was 54% vs. 53% (p = 0.99); and 10-year overall survival was 56% vs. 55% (p = 0.85). Data of clinical response (CR) were available for 78 patients (36 in the EBRT group and 42 in the EBRT+CXRT group): 12 patients were in complete CR (1 patient vs. 11 patients), 53 patients had a CR ≥50% (24 patients vs. 29 patients), and 13 patients had a CR <50% (11 patients vs. 2 patients) (p < 0.001). Of the 65 patients with CR ≥50%, 9 had an organ preservation procedure (meaning no rectal resection) taking advantage of major CR. The 10-year CRPC was 17% for patients with complete CR, 42% for patients with CR ≥50%, and 77% for patients with CR <50% (p = 0.014). In cancer of the lower rectum, CXRT increases the complete CR, turning in a significantly higher rate of long-term permanent sphincter and organ preservation.

• In regard to Hattangadi et al (Int J Radiat Oncol Biol Phys. Epub Nov 17, 2011): Accelerated Partial Breast Irradiation With Low-Dose-Rate Interstitial Implant Brachytherapy After Wide Local Excision: 12-year Outcomes From a Prospective Trial.

  Authors: Jean-Michel Hannoun-Levi, Csaba Polgar, Erik Van Limbergen

  International journal of radiation oncology, biology, physics. 83(2):481-2.

• In regard to Zhou et al "Baseline Serum Lactate Dehydrogenase Levels for Patients Treated With Intensity-Modulated Radiotherapy for Nasopharyngeal Carcinoma: A Predictor of Poor Prognosis and Subsequent Liver Metastasis" (Int J Radiat Oncol Biol Phys 2012;82:e359-e365).

  Authors: Enis Ozyar, Hale Basak Caglar, Banu Atalar

  International journal of radiation oncology, biology, physics. 83(2):482-3.

• In regard to RTOG Sarcoma Radiation Oncologists Reach Consensus on Gross Tumor Volume and Clinical Target Volume on Computed Tomographic Images for Preoperative Radiotherapy of Primary Soft Tissue Sarcoma of Extremity in Radiation Therapy Oncology Group Studies: In regard to Wang et al (Int J Radiat Oncol Biol Phys 2011;81:e525-e528).

  Authors: Brian O'Sullivan, Colleen Dickie, Charles Catton, Peter Chung, Philip Wong, Anthony Griffin, Jay Wunder, Peter Ferguson, Robert Bell

  International journal of radiation oncology, biology, physics. 83(2):483.

• Five Year Outcome of 145 Patients With Ductal Carcinoma In Situ (DCIS) After Accelerated Breast Radiotherapy.

  Authors: Raquel Ciervide, Shubhada Dhage, Amber Guth, Richard L Shapiro, Deborah M Axelrod, Daniel F Roses, Silvia C Formenti

  International journal of radiation oncology, biology, physics. 83(2):e159-64.

  Accelerated whole-breast radiotherapy (RT) with tumor bed boost in the treatment of early invasive breast cancer has demonstrated equivalent local control and cosmesis when compared with standard RT.Accelerated whole-breast radiotherapy (RT) with tumor bed boost in the treatment of early invasive breast cancer has demonstrated equivalent local control and cosmesis when compared with standard RT. Its efficacy in the treatment of ductal carcinoma in situ (DCIS) remains unknown. Patients treated for DCIS with lumpectomy and negative margins were eligible for 2 consecutive hypofractionated whole-breast RT clinical trials. The first trial (New York University [NYU] 01-51) prescribed to the whole breast 42 Gy (2.8 Gy in 15 fractions) and the second trial (NYU 05-181) 40.5 Gy (2.7 Gy in 15 fractions) with an additional daily boost of 0.5 Gy to the surgical cavity. Between 2002 and 2009, 145 DCIS patients accrued, 59 to the first protocol and 86 to the second trial. Median age was 56 years and 65% were postmenopausal at the time of treatment. Based on optimal sparing of normal tissue, 79% of the patients were planned and treated prone and 21% supine. At 5 years' median follow-up (60 months; range 2.6-105.5 months), 6 patients (4.1%) experienced an ipsilateral breast recurrence in all cases of DCIS histology. In 3/6 patients, recurrence occurred at the original site of DCIS and in the remaining 3 cases outside the original tumor bed. New contralateral breast cancers arose in 3 cases (1 DCIS and 2 invasive carcinomas). Cosmetic self-assessment at least 2 years after treatment is available in 125 patients: 91% reported good-to-excellent and 9% reported fair-to-poor outcomes. With a median follow-up of 5 years, the ipsilateral local recurrence rate is 4.1%, comparable to that reported from the NSABP (National Surgical Adjuvant Breast and Bowel Project) trials that employed 50 Gy in 25 fractions of radiotherapy for DCIS. There were no invasive recurrences. These results provide preliminary evidence that accelerated hypofractionated external beam radiotherapy is a viable option for DCIS.

• Clinical Application of a Novel Hybrid Intensity-Modulated Radiotherapy Technique for Stage III Lung Cancer and Dosimetric Comparison With Four Other Techniques.

  Authors: Wilko F A R Verbakel, Ellen van Reij, Ilonka Ladenius-Lischer, Johan P Cuijpers, Ben J Slotman, Suresh Senan

  International journal of radiation oncology, biology, physics. 83(2):e297-303.

  In large stage III lung tumors, planning delivery of doses exceeding 60 Gy can be challenging and time consuming. Intensity modulated radiation therapy (IMRT) can improve target coverage but mayIn large stage III lung tumors, planning delivery of doses exceeding 60 Gy can be challenging and time consuming. Intensity modulated radiation therapy (IMRT) can improve target coverage but may increase volumes receiving low-dose irradiation. We clinically implemented a novel hybrid IMRT (h-IMRT) technique that allowed plans to be produced quickly, and compared these plans with 4 other techniques. h-IMRT was used to treat 14 consecutive patients with planning target volumes (PTVs) exceeding 500 cm(3) (average, 779 cm(3)) with concurrent chemo-radiation therapy to 66 Gy. h-IMRT plans consisted of 2 components: an anterior-posterior/posterior-anterior/posterior-anterior (AP-PA-PA) oblique, open-field technique delivering an average dose of 58 Gy, plus a 3-field IMRT component optimized to achieve a final homogeneous dose of 66 Gy. Total lung V(20) and contralateral lung V(5) were kept as low as possible but preferably less than 35% and less than 50%, respectively. All plans were retrospectively replanned using a 5- to 9-field 3-dimensional conformal technique, full RapidArc, 6-field full IMRT, and a hybrid RapidArc (h-RapidArc) technique similar to the h-IMRT. The h-IMRT, h-RapidArc, and full RapidArc plans could be generated in less than 2 h, with the first 2 plans achieving the lowest V(5) (36%) and V(20) (30%) values together with the smallest hot spots. Both the 3-dimensional conformal and full IMRT plans occasionally led to unacceptable hot spots outside the PTV. Full RapidArc plans were fast and achieved comparable V(20) values but led to slightly higher V(5) values. Both h-IMRT and h-RapidArc permitted delivery of 66 Gy to large stage III lung tumors, and both were superior to either full IMRT or RapidArc plans for reducing lung doses. The clinical significance of small increases in V(5) during chemo-radiation therapy delivery are unknown, but the present study suggests that h-IMRT and h-RapidArc are preferable for treatment of large tumors.

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

  Authors: Rebecca K S Wong, Daniel Letourneau, Anita Varma, Jean Pierre Bissonnette, David Fitzpatrick, Daniel Grabarz, Christine Elder, Melanie Martin, Andrea Bezjak, Tony Panzarella, Mary Gospodarowicz, David A Jaffray

  International journal of radiation oncology, biology, physics.

  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 studyPURPOSE: 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.

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

  Authors: Xiaonan Sun, Chunying Yang, Hai Liu, Qi Wang, Shi-Xiu Wu, Xia Li, Tian Xie, Kathryn L Brinkman, Bin S Teh, E Brian Butler, Bo Xu, Shu Zheng

  International journal of radiation oncology, biology, physics.

  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 ionizingPURPOSE: 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.

• Role of Positron Emission Tomography-Computed Tomography in the Management of Anal Cancer.

  Authors: Massimiliano Mistrangelo, Ettore Pelosi, Marilena Bellò, Umberto Ricardi, Enrica Milanesi, Paola Cassoni, Massimo Baccega, Claudia Filippini, Patrizia Racca, Adriana Lesca, Fernando H Munoz, Gianluca Fora, Andrea Skanjeti, Francesca Cravero, Mario Morino

  International journal of radiation oncology, biology, physics.

  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 thePURPOSE: 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.

• Predictors of Toxicity After Image-guided High-dose-rate Interstitial Brachytherapy for Gynecologic Cancer.

  Authors: Larissa J Lee, Akila N Viswanathan

  International journal of radiation oncology, biology, physics.

  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.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.

  Authors: Sebastian Reuther, Elisabeth Metzke, Michael Bonin, Cordula Petersen, Ekkehard Dikomey, Annette Raabe

  International journal of radiation oncology, biology, physics.

  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 humanPURPOSE: 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.

• Risk of Radiation Retinopathy in Patients With Orbital and Ocular Lymphoma.

  Authors: Megha Kaushik, Jose S Pulido, Steven E Schild, Scott Stafford

  International journal of radiation oncology, biology, physics.

  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 isPURPOSE: 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.

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

  Authors: Anders Jakobsen, John Ploen, Té Vuong, Ane Appelt, Jan Lindebjerg, Soren R Rafaelsen

  International journal of radiation oncology, biology, physics.

  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.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/m(2) 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.

  Authors: Jeffrey Y C Wong, Stephen Forman, George Somlo, Joseph Rosenthal, An Liu, Timothy Schultheiss, Eric Radany, Joycelynne Palmer, Anthony Stein

  International journal of radiation oncology, biology, physics.

  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 ofPURPOSE: 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.

• 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.

  Authors: Ingeborg Tinhofer, Tsvetana Hristozova, Carmen Stromberger, Ulrich Keilhoiz, Volker Budach

  International journal of radiation oncology, biology, physics.

  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 asPURPOSE: 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.

• 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).

  Authors: Sunao Tokumaru, Takafumi Toita, Masahiko Oguchi, Tatsuya Ohno, Shingo Kato, Yuzuru Niibe, Tomoko Kazumoto, Takeshi Kodaira, Masaaki Kataoka, Naoto Shikama, Masahiro Kenjo, Chikako Yamauchi, Osamu Suzuki, Hideyuki Sakurai, Teruki Teshima, Yoshikazu Kagami, Takashi Nakano, Masahiro Hiraoka, Norio Mitsuhashi, Sho Kudo

  International journal of radiation oncology, biology, physics.

  PURPOSE: To investigate pelvic insufficiency fractures (IF) after definitive pelvic radiation therapy for early-stage uterine cervical cancer, by analyzing subjects of a prospective,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.

• Regional Normal Lung Tissue Density Changes in Patients Treated With Stereotactic Body Radiation Therapy for Lung Tumors.

  Authors: Quentin Diot, Brian Kavanagh, Tracey Schefter, Laurie Gaspar, Kelly Stuhr, Moyed Miften

  International journal of radiation oncology, biology, physics.

  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). METHODSPURPOSE: 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 cm(3)) and with >3 fractions of 6 to 12.5 Gy (median, 9 Gy; average tumor volume, 30 ± 40 cm(3)), 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.

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

  Authors: Luciana Caravatta, Gilbert D A Padula, Gabriella Macchia, Gabriella Ferrandina, Pierluigi Bonomo, Francesco Deodato, Mariangela Massaccesi, Samantha Mignogna, Rosa Tambaro, Marco Rossi, Mariano Flocco, Andrea Scapati, Giovanni Scambia, Fabio Pacelli, Vincenzo Valentini, Numa Cellini, Alessio G Morganti

  International journal of radiation oncology, biology, physics.

  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 3PURPOSE: 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.

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

  Authors: Lisa Capelle, Heather Warkentin, Marc Mackenzie, Kurian Joseph, Zsolt Gabos, Nadeem Pervez, Keith Tankel, Susan Chafe, John Amanie, Sunita Ghosh, Matthew Parliament, Bassam Abdulkarim

  International journal of radiation oncology, biology, physics.

  PURPOSE: We investigated whether treatment-planning system (TPS)-calculated dose accurately reflects skin dose received for patients receiving adjuvant breast radiotherapy (RT) with standardPURPOSE: 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 skin(V50) (1.4% vs 5.9%, respectively; P=.001) but higher skin(V40) and skin(V30) (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.

• Predicting Pneumonitis Risk: A Dosimetric Alternative to Mean Lung Dose.

  Authors: Susan L Tucker, Radhe Mohan, Raweewan Liengsawangwong, Mary K Martel, Zhongxing Liao

  International journal of radiation oncology, biology, physics.

  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 amongPURPOSE: 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").

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