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

Effect of Hyperoxygenation on Tissue pO2 and Its Effect on Radiotherapeutic Efficacy of Orthotopic F98 Gliomas - Corrected Proof

2010-09-01

Purpose: Lack of methods for repeated assessment of tumor pO2 limits the ability to test and optimize hypoxia-modifying procedures being developed for clinical applications. We report repeated measurements of orthotopic F98 tumor pO2 and relate this to the effect of carbogen inhalation on tumor growth when combined with hypofractionated radiotherapy.Methods and Materials: Electron paramagnetic resonance (EPR) oximetry was used for repeated measurements of tumor and contralateral brain pO2 in rats during 30% O2 and carbogen inhalation for 5 consecutive days. The T1-enhanced volumes and diffusion coefficients of the tumors were assessed by magnetic resonance imaging (MRI). The tumors were irradiated with 9.3 Gy x 4 fractions in rats breathing 30% O2 or carbogen to determine the effect on tumor growth.Results: The pretreatment F98 tumor pO2 varied between 8 and 16 mmHg, while the contralateral brain had 41 to 45 mmHg pO2 during repeated measurements. Carbogen breathing led to a significant increase in tumor and contralateral brain pO2; however, this effect declined over days. Irradiation of the tumors in rats breathing carbogen resulted in a significant decrease in tumor growth and an increase in the diffusion coefficient measured by MRI.Conclusions: The results provide quantitative measurements of the effect of carbogen inhalation on intracerebral tumor pO2 and its effect on therapeutic outcome. Such direct repeated pO2 measurements by EPR oximetry can provide temporal information that could be used to improve therapeutic outcome by scheduling doses at times of improved tumor oxygenation. EPR oximetry is currently being tested for clinical applications.

ACR Appropriateness Criteria® on Induction and Adjuvant Therapy for Stage N2 Non–Small-Cell Lung Cancer: Expert Panel on Radiation Oncology–Lung - Corrected Proof

2010-09-01

“The American College of Radiology seeks and encourages collaboration with other organizations on the development of the ACR Appropriateness Criteria through society representation on expert panels. Participation by representatives from collaborating societies on the expert panel does not necessarily imply society endorsement of the final document.”

Technique for Targeting Arteriovenous Malformations Using Frameless Image-Guided Robotic Radiosurgery - Corrected Proof

2010-08-31

Purpose: To integrate three-dimensional (3D) digital rotation angiography (DRA) and two-dimensional (2D) digital subtraction angiography (DSA) imaging into a targeting methodology enabling comprehensive image-guided robotic radiosurgery of arteriovenous malformations (AVMs).Methods and Materials: DRA geometric integrity was evaluated by imaging a phantom with embedded markers. Dedicated DSA acquisition modes with preset C-arm positions were configured. The geometric reproducibility of the presets was determined, and its impact on localization accuracy was evaluated. An imaging protocol composed of anterior-posterior and lateral DSA series in combination with a DRA run without couch displacement between acquisitions was introduced. Software was developed for registration of DSA and DRA (2D-3D) images to correct for: (a) small misalignments of the C-arm with respect to the estimated geometry of the set positions and (b) potential patient motion between image series. Within the software, correlated navigation of registered DRA and DSA images was incorporated to localize AVMs within a 3D image coordinate space. Subsequent treatment planning and delivery followed a standard image-guided robotic radiosurgery process.Results: DRA spatial distortions were typically smaller than 0.3 mm throughout a 145-mm × 145-mm × 145-mm volume. With 2D-3D image registration, localization uncertainties resulting from the achievable reproducibility of the C-arm set positions could be reduced to about 0.2 mm. Overall system-related localization uncertainty within the DRA coordinate space was 0.4 mm. Image-guided frameless robotic radiosurgical treatments with this technique were initiated.Conclusions: The integration of DRA and DSA into the process of nidus localization increases the confidence with which radiosurgical ablation of AVMs can be performed when using only an image-guided technique. Such an approach can increase patient comfort, decrease time pressure on clinical and technical staff, and possibly reduce the number of cerebral angiograms needed for a particular patient.

Mometasone Furoate Effect on Acute Skin Toxicity in Breast Cancer Patients Receiving Radiotherapy: A Phase III Double-Blind, Randomized Trial from the North Central Cancer Treatment Group N06C4 - Corrected Proof

2010-08-27

Purpose: A two-arm, double-blind, randomized trial was performed to evaluate the effect of 0.1% mometasone furoate (MMF) on acute skin-related toxicity in patients undergoing breast or chest wall radiotherapy.Methods and Materials: Patients with ductal carcinoma in situ or invasive breast carcinoma who were undergoing external beam radiotherapy to the breast or chest wall were randomly assigned to apply 0.1% MMF or placebo cream daily. The primary study endpoint was the provider-assessed maximal grade of Common Terminology Criteria for Adverse Events, version 3.0, radiation dermatitis. The secondary endpoints included provider-assessed Common Terminology Criteria for Adverse Events Grade 3 or greater radiation dermatitis and adverse event monitoring. The patient-reported outcome measures included the Skindex-16, the Skin Toxicity Assessment Tool, a Symptom Experience Diary, and a quality-of-life self-assessment. An assessment was performed at baseline, weekly during radiotherapy, and for 2 weeks after radiotherapy.Results: A total of 176 patients were enrolled between September 21, 2007, and December 7, 2007. The provider-assessed primary endpoint showed no difference in the mean maximum grade of radiation dermatitis by treatment arm (1.2 for MMF vs. 1.3 for placebo; p = .18). Common Terminology Criteria for Adverse Events toxicity was greater in the placebo group (p = .04), primarily from pruritus. For the patient-reported outcome measures, the maximum Skindex-16 score for the MMF group showed less itching (p = .008), less irritation (p = .01), less symptom persistence or recurrence (p = .02), and less annoyance with skin problems (p = .04). The group's maximal Skin Toxicity Assessment Tool score showed less burning sensation (p = .02) and less itching (p = .002).Conclusion: Patients receiving daily MMF during radiotherapy might experience reduced acute skin toxicity compared with patients receiving placebo.

Primary Analysis of a Phase II Randomized Trial Radiation Therapy Oncology Group (RTOG) 0212: Impact of Different Total Doses and Schedules of Prophylactic Cranial Irradiation on Chronic Neurotoxicity and Quality of Life for Patients with Limited-Disease Small-Cell Lung Cancer - Corrected Proof

2010-08-27

Purpose: To determine the effect of dose and fractionation schedule of prophylactic cranial irradiation (PCI) on the incidence of chronic neurotoxicity (CNt) and changes in quality of life for selected patients with limited-disease small-cell lung cancer (LD SCLC).Methods and Materials: Patients with LD SCLC who achieved a complete response after chemotherapy and thoracic irradiation were eligible for randomization to undergo PCI to a total dose of 25 Gy in 10 daily fractions (Arm 1) vs. the experimental cohort of 36 Gy. Those receiving 36 Gy underwent a secondary randomization between daily 18 fractions (Arm 2) and twice-daily 24 fractions (Arm 3). Enrolled patients participated in baseline and follow-up neuropsychological test batteries along with quality-of-life assessments.Results: A total of 265 patients were accrued, with 131 in Arm 1, 67 in Arm 2, and 66 in Arm 3 being eligible. There are 112 patients (42.2%) alive with 25.3 months of median follow-up. There were no significant baseline differences among groups regarding quality-of-life measures and one of the neuropsychological tests, namely the Hopkins Verbal Learning Test. However, at 12 months after PCI there was a significant increase in the occurrence of CNt in the 36-Gy cohort (p = 0.02). Logistic regression analysis revealed increasing age to be the most significant predictor of CNt (p = 0.005).Conclusions: Because of the increased risk of developing CNt in study patients with 36 Gy, a total PCI dose of 25 Gy remains the standard of care for patients with LD SCLC attaining a complete response to initial chemoradiation.

Data-Driven Approach to Generating Achievable Dose–Volume Histogram Objectives in Intensity-Modulated Radiotherapy Planning - Corrected Proof

2010-08-27

Purpose: To propose a method of intensity-modulated radiotherapy (IMRT) planning that generates achievable dose–volume histogram (DVH) objectives using a database containing geometric and dosimetric information of previous patients.Methods and Materials: The overlap volume histogram (OVH) is used to compare the spatial relationships between the organs at risk and targets of a new patient with those of previous patients in a database. From the OVH analysis, the DVH objectives of the new patient were generated from the database and used as the initial planning goals. In a retrospective OVH-assisted planning demonstration, 15 patients were randomly selected from a database containing clinical plans (CPs) of 91 previous head-and-neck patients treated by a three-level IMRT-simultaneous integrated boost technique. OVH-assisted plans (OPs) were planned in a leave-one-out manner by a planner who had no knowledge of CPs. Thus, DVH objectives of an OP were generated from a subdatabase containing the information of the other 90 patients. Those DVH objectives were then used as the initial planning goals in IMRT optimization. Planning efficiency was evaluated by the number of clicks of the “Start Optimization” button in the course of planning. Although the Pinnacle3 treatment planning system allows planners to interactively adjust the DVH parameters during optimization, planners in our institution have never used this function in planning.Results: The average clicks required for completing the CP and OP was 27.6 and 1.9, respectively (p <.00001); three OPs were finished within a single click. Ten more patient's cord + 4 mm reached the sparing goal D0.1cc <44 Gy (p <.0001), where D0.1cc represents the dose corresponding to 0.1 cc. For planning target volume uniformity, conformity, and other organ at risk sparing, the OPs were at least comparable with the CPs. Additionally, the averages of D0.1cc to the cord + 4 mm decreased by 6.9 Gy (p <.0001); averages of D0.1cc to the brainstem decreased by 7.7 Gy (p <.005). The averages of V(30 Gy) to the contralateral parotid decreased by 8.7% (p <.0001), where V(30 Gy) represents the percentage volume corresponding to 30 Gy.Conclusion: The method heralds the possibility of automated IMRT planning.

Patterns of Response After Preoperative INTENSITY-MODULATED RADIATION THERAPY and capecitabine/oxaliplatin in Rectal Cancer: Is There Still a Place for Ecoendoscopic Ultrasound? - Corrected Proof

2010-08-27

Purpose: The main goals of preoperative chemoradiotherapy (CHRT) in rectal cancer are to achieve pathological response and to ensure tumor control with functional surgery when possible. Assessment of the concordance between clinical and pathological responses is necessary to make decisions regarding alternative conservative procedures. The present study evaluates the patterns of response after a preoperative CHRT regimen, and the value of endoscopic ultrasound (EUS) in assessing response.Methods and Materials: A total of 51 EUS-staged T3 to T4 and/or N0 to N+ rectal cancer patients received preoperative CHRT (intensity-modulated radiation therapy and capecitabine/oxaliplatin (XELOX) followed by radical resection. Clinical response was assesed by EUS. Rates of pathological tumor regression grade (TRG) and lymph node (LN) involvement were determined in the surgical specimen. Clinical and pathological responses were compared, and the accuracy of EUS in assessing response was calculated.Results: Twenty-four patients (45%) achieved a major pathological response (complete or >95% pathological response (TRG 3+/4)). Sensitivity, specificity, negative predictive value, and positive predictive value of EUS in predicting pathological T response after preoperative CHRT were 77.8%, 37.5%, 60%, and 58%, respectively. The EUS sensitivity, specificity, negative predictive value, and positive predictive value for nodal staging were 44%, 88%, 88%, and 44%, respectively. Furthermore, EUS after CHRT accurately predicted the absence of LN involvement in 7 of 7 patients (100%) with major pathological response of the primary tumor.Conclusion: Preoperative IMRT with concomitant XELOX induces favorable rates of major pathological response. EUS has a limited ability to predict primary tumor response after preoperative CHRT, but it is useful for accurately determining LN status. EUS may have a potential value in identifying patients with a very low risk of LN involvement in association with a good pathological response as potential candidates for conservative local surgical protocols.

Imaging Opportunities in Radiation Oncology - Corrected Proof

2010-08-27

Interdisciplinary efforts may significantly affect the way that clinical knowledge and scientific research related to imaging impact the field of Radiation Oncology. This report summarizes the findings of an intersociety workshop held in October 2008, with the express purpose of exploring “Imaging Opportunities in Radiation Oncology.” Participants from the American Society for Radiation Oncology (ASTRO), National Institutes of Health (NIH), Radiological Society of North America (RSNA), American Association of physicists in Medicine (AAPM), American Board of Radiology (ABR), Radiation Therapy Oncology Group (RTOG), European Society for Therapeutic Radiology and Oncology (ESTRO), and Society of Nuclear Medicine (SNM) discussed areas of education, clinical practice, and research that bridge disciplines and potentially would lead to improved clinical practice. Findings from this workshop include recommendations for cross-training opportunities within the allowed structured of Radiology and Radiation Oncology residency programs, expanded representation of ASTRO in imaging related multidisciplinary groups (and reciprocal representation within ASTRO committees), increased attention to imaging validation and credentialing for clinical trials (e.g., through the American College of Radiology Imaging Network (ACRIN)), and building ties through collaborative research as well as smaller joint workshops and symposia.

Accelerated Partial Breast Irradiation for Pure Ductal Carcinoma in Situ - Corrected Proof

2010-08-27

Purpose: To report outcomes for ductal carcinoma in situ (DCIS) treated with breast-conserving therapy using accelerated partial breast irradiation (APBI).Methods and Materials: From March 2001 to February 2009, 53 patients with Stage 0 breast cancer were treated with breast conserving surgery and adjuvant APBI. Median age was 62 years. All patients underwent excision with margins negative by ≥1 mm before adjuvant radiotherapy (RT). A total of 39 MammoSite brachytherapy (MS) patients and 14 three-dimensional conformal external beam RT (3DCRT) patients were treated to the lumpectomy bed alone with 34 Gy and 38.5 Gy, respectively. Of the DCIS cases, 94% were mammographically detected. All patients with calcifications had either specimen radiography or postsurgical mammography confirmation of clearance. Median tumor size was 6 mm, and median margin distance was 5 mm. There were no statistically significant differences according to APBI method for race/ethnicity, tumor detection method, tumor grade, estrogen receptor (ER) status, or use of tamoxifen (p = NS). Recurrence and survival were calculated using the Kaplan–Meier method. Cosmesis was scored by the Harvard criteria.Results: With a median follow-up of 3.6 years (range, 0.4–6.3 years), the overall and cause-specific survival rates were 98% and 100%, respectively. Three-year actuarial ipsilateral breast tumor recurrence was 2%. One failure was observed at the resection bed 11 months post-RT. No other elsewhere breast failures, regional recurrences, or distant metastases were noted. Cosmesis was excellent or good in 92.4% of cases, with no statistically significant differences according to the APBI method (92.3% with MammoSite and 92.8% with 3DCRT; p = 0.649).Conclusions: APBI as part of breast-conserving therapy for pure DCIS was associated with excellent local control and survival rates, with the vast majority of patients having good to excellent cosmesis. This finding supports the recent analysis by the American Society of Breast Surgeons on a subset of DCIS patients treated efficaciously with APBI.

Parametrial Boost Using Midline Shielding Results in an Unpredictable Dose to Tumor and Organs at Risk in Combined External Beam Radiotherapy and Brachytherapy for Locally Advanced Cervical Cancer - Corrected Proof

2010-08-27

Purpose: Midline-blocked boost (MBB) fields are frequently used in the treatment of locally advanced cervical cancer. The purpose of this study was to evaluate the dose contribution from MBBs to tumor and organs at risk.Methods and Materials: Six patients with locally advanced cervical cancer (IIB–IIIB) treated with definitive chemoradiotherapy and magnetic resonance imaging (MRI)–guided brachytherapy were analyzed. A three-phase plan was modeled: 45 Gy (1.8 Gy per fraction) four-field box, 9 Gy (1.8 Gy per fraction) MBB (midline-shielded anteroposterior/posteroanterior fields), and intracavitary MRI–guided brachytherapy boost of 28 Gy (7 Gy per fraction). Midline shields 3, 4, and 5 cm wide were simulated for each patient. Brachytherapy and MBB plans were volumetrically summed. The rectum, sigmoid, and bladder minimum dose in the most exposed 2 cm3 of an organ at risk (D2 cc) and high-risk clinical target volume (HR-CTV) and intermediate-risk clinical target volume (IR-CTV) D90 and D100 were evaluated. The intended HR-CTV D90 was 85 Gy or greater, and the intended IR-CTV D90 was greater than 60 Gy.Results: After a 4-cm MBB, HR-CTV D90 remained lower than 85 Gy in all cases (mean, 74 Gy; range, 64–82 Gy). High-risk clinical target volume (85 Gy) coverage increased slightly from 73% (range, 64–82%) to 78% (range, 69–88%). Mean IR-CTV D90 increased from 56 Gy (range, 53–64 Gy) to 62 Gy (range, 59–67 Gy). Intermediate-risk clinical target volume 60-Gy dose coverage increased from 81% (range, 72–96%) to 96% (range, 90–100%). The mean volume irradiated to 85 Gy increased by 14 cm3 (range, 10–22 cm3), whereas the volume irradiated to 60 Gy increased from 276 cm3 (range, 185–417 cm3) to 592 cm3 (range, 385–807 cm3). Bladder, rectum, or sigmoid D2 cc increased by more than 50% of the boost dose in 4 of 6 patients.Conclusions: Midline-blocked boosts contribute substantial dose to rectum, sigmoid, and bladder D2 cc. HR-CTV dose and 85-Gy coverage remain compromised in large tumors despite MBB. IR-CTV 60-Gy coverage improved at the expense of a considerable increase in volume of normal tissue irradiated to 60 Gy.

Clinical Outcome of Hypofractionated Stereotactic Radiotherapy for Abdominal Lymph Node Metastases - Corrected Proof

2010-08-27

Purpose: We report the medium-term clinical outcome of hypofractionated stereotactic body radiotherapy (SBRT) in a series of patients with either a solitary metastasis or oligometastases from different tumors to abdominal lymph nodes.Methods and Materials: Between January 2006 and June 2009, 19 patients with unresectable nodal metastases in the abdominal retroperitoneal region were treated with SBRT. Of the patients, 11 had a solitary nodal metastasis and 8 had a dominant nodal lesion as part of oligometastatic disease, defined as up to five metastases. The dose prescription was 45 Gy to the clinical target volume in six fractions. The prescription had to be downscaled by 10% to 20% in 6 of 19 cases to keep within dose/volume constraints. The first 11 patients were treated with three-dimensional conformal techniques and the last 8 by volumetric intensity-modulated arc therapy. Median follow-up was 1 year.Results: Of 19 patients, 2 had a local progression at the site of SBRT; both also showed concomitant tumor growth at distant sites. The actuarial rate of freedom from local progression was 77.8% ± 13.9% at both 12 and 24 months. Eleven patients showed progressive local and/or distant disease at follow-up. The 12- and 24-month progression-free survival rates were 29.5% ± 13.4% and 19.7% ± 12.0%, respectively. The number of metastases (solitary vs. nonsolitary oligometastases) emerged as the only significant variable affecting progression-free survival (p < 0.0004). Both acute and chronic toxicities were minimal.Conclusions: Stereotactic body radiotherapy for metastases to abdominal lymph nodes was shown to be feasible with good clinical results in terms of medium-term local control and toxicity rates. Even if most patients eventually show progressive disease at other sites, local control achieved by SBRT may be potentially significant for preserving quality of life and delaying further chemotherapy.

Single-Dose Versus Fractionated Stereotactic Radiotherapy for Brain Metastases - Corrected Proof

2010-08-27

Purpose: To evaluate the efficacy of stereotactic radiotherapy in patients with brain metastases by comparing two different treatment regimens, single-dose radiosurgery (SRS) and fractionated stereotactic radiotherapy (FSRT).Methods and Materials: Between November 2003 and December 2008, 98 patients with brain metastases were included. Fifty-eight patients were treated with SRS, and forty were treated with FSRT. Fractionated stereotactic radiotherapy was used for large lesions or lesions located near critical structures. The median doses were 20 Gy for the SRS group and 36 Gy in 6 fractions for the FSRT group.Results: With a median follow-up period of 7 months, the median survival was 7 months for all patients, with a median of 6 months for the SRS group and 8 months for the FSRT group (p = 0.89). Local progression–free survival (LPFS) rates at 6 months and 1 year were 81% and 71%, respectively, for the SRS group and 97% and 69%, respectively, for the FSRT group (p = 0.31). Despite the fact that FSRT was used for large lesions and lesions in adverse locations, LPFS was not inferior to SRS. Toxicity was more frequently observed in the SRS group than in the FSRT group (17% vs. 5%, p = 0.05).Conclusions: Because patients treated with FSRT exhibited similar survival times and LPFS rates with a lower risk of toxicity in comparison to those treated with SRS, despite the fact that FSRT was used for large lesions and lesions in adverse locations, we find that FSRT can particularly be beneficial for patients with large lesions or lesions located near critical structures. Further investigation is warranted to determine the optimal dose/fractionation.

Intrafractional Target Motions and Uncertainties of Treatment Setup Reference Systems in Accelerated Partial Breast Irradiation - Corrected Proof

Ning J. Yue, Sharad Goyal, Jinghao Zhou, Atif J. Khan, Bruce G. Haffty — 2010-08-27

Purpose: This study investigated the magnitude of intrafractional motion and level of accuracy of various setup strategies in accelerated partial breast irradiation (APBI) using three-dimensional conformal external beam radiotherapy.Methods and Materials: At lumpectomy, gold fiducial markers were strategically sutured to the surrounding walls of the cavity. Weekly fluoroscopy imaging was conducted at treatment to investigate the respiration-induced target motions. Daily pre- and post-RT kV imaging was performed, and images were matched to digitally reconstructed radiographs based on bony anatomy and fiducial markers, respectively, to determine the intrafractional motion magnitudes over the course of treatment. The positioning differences of the laser tattoo- and the bony anatomy-based setups compared with those of the marker-based setup (benchmark) were also determined. The study included 21 patients.Results: Although lung exhibited significant motion, the average marker motion amplitude on the fluoroscopic image was about 1 mm. Over a typical treatment time period, average intrafractional motion magnitude was 4.2 mm and 2.6 mm based on the marker and bony anatomy matching, respectively. The bony anatomy- and laser tattoo-based interfractional setup errors, with respect to the fiducial marker-based setup, were 7.1 and 9.0 mm, respectively.Conclusions: Respiration has limited effects on the target motion during APBI. Bony anatomy-based treatment setup improves the accuracy relative to that of the laser tattoo-based setup approach. Since fiducial markers are sutured directly to the surgical cavity, the marker-based approach can further improve the interfractional setup accuracy. On average, a seroma cavity exhibits intrafractional motion of more than 4 mm, a magnitude that is larger than that which is otherwise derived based on bony anatomy matching. A seroma-specific marker-based approach has the potential to improve treatment accuracy by taking the true inter- and intrafractional motions into consideration.

Predicted Risk of Radiation-Induced Cancers after Involved Field and Involved Node Radiotherapy with or without Intensity Modulation for Early-Stage Hodgkin Lymphoma in Female Patients - Corrected Proof

Damien C. Weber, Safora Johanson, Nicolas Peguret, Luca Cozzi, Dag R. Olsen — 2010-08-27

Purpose: To assess the excess relative risk (ERR) of radiation-induced cancers (RIC) in female patients with Hodgkin lymphoma (HL) female patients treated with conformal (3DCRT), intensity modulated (IMRT), or volumetric modulated arc (RA) radiation therapy.Methods and Materials: Plans for 10 early-stage HL female patients were computed for 3DCRT, IMRT, and RA with involved field RT (IFRT) and involvednode RT (INRT) radiation fields. Organs at risk dose--volume histograms were computed and inter-compared for IFRT vs. INRT and 3DCRT vs. IMRT/RA, respectively. The ERR for cancer induction in breasts, lungs, and thyroid was estimated using both linear and nonlinear models.Results: The mean estimated ERR for breast, lung, and thyroid were significantly lower (p < 0.01) with INRT than with IFRT planning, regardless of the radiation delivery technique used, assuming a linear dose-risk relationship. We found that using the nonlinear model, the mean ERR values were significantly (p < 0.01) increased with IMRT or RA compared to those with 3DCRT planning for the breast, lung, and thyroid, using an IFRT paradigm. After INRT planning, IMRT or RA increased the risk of RIC for lung and thyroid only.Conclusions: In this comparative planning study, using a nonlinear dose--risk model, IMRT or RA increased the estimated risk of RIC for breast, lung, and thyroid for HL female patients. This study also suggests that INRT planning, compared to IFRT planning, may reduce the ERR of RIC when risk is predicted using a linear model. Observing the opposite effect, with a nonlinear model, however, questions the validity of these biologically parameterized models.

Renal Shielding and Dosimetry for Patients with Severe Systemic Sclerosis Receiving Immunoablation with Total Body Irradiation in the Scleroderma: Cyclophosphamide or Transplantation Trial - Corrected Proof

2010-08-27

Purpose: To describe renal shielding techniques and dosimetry in delivering total body irradiation (TBI) to patients with severe systemic sclerosis (SSc) enrolled in a hematopoietic stem cell transplant protocol.Methods and Materials: The Scleroderma: Cyclophosphamide or Transplantation (SCOT) protocol uses a lymphoablative preparative regimen including 800 cGy TBI delivered in two 200-cGy fractions twice a day before CD34+ selected autologous hematopoietic stem cell transplantation. Lung and kidney doses are limited to 200 cGy to protect organs damaged by SSc. Kidney block proximity to the spinal cord was investigated, and guidelines were developed for acceptable lumbar area TBI dosing. Information about kidney size and the organ shifts from supine to standing positions were recorded using diagnostic ultrasound (US). Minimum distance between the kidney blocks (dkB) and the lumbar spine region dose was recorded, and in vivo dosimetry was performed at several locations to determine the radiation doses delivered.Results: Eleven patients were treated at our center with an anteroposterior (AP)/posteroanterior (PA) TBI technique. A 10% to 20% dose inhomogeneity in the lumbar spine region was achieved with a minimum kidney block separation of 4 to 5 cm. The average lumbar spine dose was 179.6 ± 18.1 cGy, with an average dkB of 5.0 ± 1.0 cm. Kidney block shield design was accomplished using a combination of US and noncontrast computerized tomography (CT) or CT imaging alone. The renal US revealed a wide range of kidney displacement from upright to supine positions. Overall, the average in vivo dose for the kidney prescription point was 193.4 ± 5.1 cGy.Conclusions: The dose to the kidneys can be attenuated while maintaining a 10% to 20% dose inhomogeneity in the lumbar spine area. Kidneys were localized more accurately using both US and CT imaging. With this technique, renal function has been preserved, and the study continues to enroll patients.

The Use of the Active Breathing Coordinator throughout Radical Non–small-cell Lung Cancer (NSCLC) Radiotherapy - Corrected Proof

2010-08-27

Purpose: To assess feasibility and reproducibility of an Active Breathing Coordinator (ABC) used throughout radical radiotherapy for non–small-cell lung cancer, and compare lung dosimetric parameters between free-breathing and ABC plans.Methods and Materials: A total of 18 patients, recruited into an approved study, had free-breathing and ABC breath-hold treatment plans generated. Lung volume, the percentage volume of lung treated to a dose of ≥20 Gy (V20), and mean lung dose (MLD) were compared. Treatment (64 Gy in 32 fractions, 5 days/week) was delivered in breath-hold. Repeat breath-hold computed tomography scans were used to assess change in gross tumor volume (GTV) size and position. Setup error was also measured and potential GTV-planning target volume (PTV) margins calculated.Results: Seventeen of 18 patients completed radiotherapy using ABC daily. Intrafraction tumor position was consistent, but interfraction variation had mean (range) values of 5.1 (0–25), 3.6 (0–9.7), and 3.5 (0–16.6) mm in the superoinferior (SI), right-left (RL), and anteroposterior (AP) directions, respectively. Tumor moved partially outside the PTV in 5 patients. Mean reduction in GTV from planning to end of treatment was 25% (p = 0.003). Potentially required PTV margins were 18.1, 11.9, and 11.9 mm in SI, RL, and AP directions. ABC reduced V20 by 13% (p = 0.0001), V13 by 12% (p = 0.001), and MLD by 13% (p < 0.001) compared with free-breathing; lung volume increased by 41% (p < 0.001).Conclusions: Clinically significant movements of GTV were seen during radiotherapy for non–small-cell lung cancer using ABC. Image guidance is recommended with ABC. The use of ABC can reduce dose volume parameters determining lung toxicity, and might allow for equitoxic radiotherapy dose escalation.

Determination of the Absorbed Dose Rate to Water for the 18-mm Helmet of a Gamma Knife - Corrected Proof

2010-08-27

Purpose: To measure the absorbed dose rate to water of 60Co gamma rays of a Gamma Knife Model C using water-filled phantoms (WFP).Methods and Materials: Spherical WFP with an equivalent water depth of 5, 7, 8, and 9 cm were constructed. The dose rates at the center of an 18-mm helmet were measured in an 8-cm WFP (WFP-3) and two plastic phantoms. Two independent measurement systems were used: one was calibrated to an air kerma (Set I) and the other was calibrated to the absorbed dose to water (Set II). The dose rates of WFP-3 and the plastic phantoms were converted to dose rates for an 8-cm water depth using the attenuation coefficient and the equivalent water depths.Results: The dose rate measured at the center of WFP-3 using Set II was 2.2% and 1.0% higher than dose rates measured at the center of the two plastic phantoms. The measured effective attenuation coefficient of Gamma Knife photon beam in WFPs was 0.0621 cm−1. After attenuation correction, the difference between the dose rate at an 8-cm water depth measured in WFP-3 and dose rates in the plastic phantoms was smaller than the uncertainty of the measurements.Conclusions: Systematic errors related to the characteristics of the phantom materials in the dose rate measurement of a Gamma Knife need to be corrected for. Correction of the dose rate using an equivalent water depth and attenuation provided results that were more consistent.

Three or Four Fractions of 4–5 Gy per Week in Postoperative High-Dose-Rate Brachytherapy for Endometrial Carcinoma - Corrected Proof

2010-08-27

Purpose: To evaluate the results of high-dose-rate brachytherapy (HDRBT) using a schedule of three or four fractions per week, when possible, in 89 patients on local control and toxicity in postoperative treatment of endometrial carcinoma. The effect of the overall HDRBT treatment time (OTT) on toxicity was also evaluated.Patients and Methods: Fédération Internationale de Gynécologie Obstétrique Stage: 24 IB, 45 IC, 4 IIA, 6 IIB, 4 IIIA, 2 IIIB, and 4 IIIC. Radiotherapy: Group 1—67 of 89 patients received external beam irradiation (EBI; 44–50 Gy) plus HDRBT (3 fractions of 4–6 Gy); Group 2—22 of 89 patients received HDRBT alone (6 fractions of 4–5 Gy). OTT: Group 1—HDRBT was completed in a median of 5 days in 32 patients and in >5 days in 35; Group 2—HDRBT was completed in <15 days in 11 patients and in ≥16 days in 11. Toxicity was evaluated using Radiation Therapy Oncology Group scores and the bioequivalent dose (BED) study was performed in vaginal mucosa surface. Statistics included Student's t test, chi-square test, and receiving operator curves.Results: With a mean follow-up of 31 months (range, 6–70), 1 of 89 patients had vaginal relapse. Early toxicity appeared in 8 of 89 (9%) patients and was resolved. Late toxicity appeared in 13/89 (14%): vaginal nine Grade 1, three Grade 2, one Grade 4; bladder two Grade 2; rectal three Grade 1, one Grade 2. No differences were found in relation to OTT in Groups 1 and 2. Mean BED was 88.48 Gy in Group 1 and 165.28 Gy in Group 2. Cases with Grade 2 late vaginal toxicity received >75 Gy after EBI and >165 Gy in Group 2.Conclusions: Three fractions of 4–5 Gy in 3–5 days after EBI or 6 fractions in <15 days in patients receiving HDRBT alone was a safe treatment in relation to toxicity and local control. Vaginal surface BED less than 75 Gy after EBI and less than 160 Gy in HDRBT alone may be safe to avoid G2 toxicity.

Comparison of Nodal Risk Formula and MR Lymphography for Predicting Lymph Node Involvement in Prostate Cancer - Corrected Proof

2010-08-27

Purpose: To compare the nodal risk formula (NRF) as a predictor for lymph node (LN) metastasis in patients with prostate cancer with magnetic resonance lymphography (MRL) using Ultrasmall Super-Paramagnetic particles of Iron Oxide (USPIO) and with histology as gold standard.Methods and Materials: Logistic regression analysis was performed with the results of histopathological evaluation of the LN as dependent variable and the nodal risk according to the NRF and the result of MRL as independent input variables. Receiver operating characteristic (ROC) analysis was performed to assess the performance of the models.Results: The analysis included 375 patients. In the single-predictor regression models, the NRF and MRL results were both significantly (p <0.001) predictive of the presence of LN metastasis. In the models with both predictors included, NRF was nonsignificant (p = 0.126), but MRL remained significant (p <0.001). For NRF, sensitivity was 0.79 and specificity was 0.38; for MRL, sensitivity was 0.82 and specificity was 0.93. After a negative MRL result, the probability of LN metastasis is 4% regardless of the NRF result. After a positive MRL, the probability of having LN metastasis is 68%.Conclusions: MRL is a better predictor of the presence of LN metastasis than NRF. Using only the NRF can lead to a significant overtreatment on the pelvic LN by radiation therapy. When the MRL result is available, the NRF is no longer of added value.

Development of Late Toxicity and International Prostate Symptom Score Resolution After External-Beam Radiotherapy Combined with Pulsed Dose Rate Brachytherapy for Prostate Cancer - Corrected Proof

2010-08-27

Purpose: To investigate the development of gastrointestinal (GI) toxicity, genitourinary (GU) toxicity, erectile dysfunction, and International Prostate Symptom Score (IPSS) resolution in a cohort of patients treated with external-beam radiotherapy (EBRT) followed by a brachytherapy pulsed dose rate (PDR) boost.Methods and Materials: Between 2002 and 2008, 110 patients were treated with 46-Gy EBRT followed by PDR brachytherapy (24.96–28.80 Gy). The investigated outcome variables, GI toxicity, GU toxicity, erectile dysfunction, and IPSS were prospectively scored at several time points during follow-up. Association between time (as continuous and categorical variable) and the outcome variables was assessed using generalized linear models.Results: No statistically significant association was found between time (continuous) and GI toxicity (odds ratio [OR], 0.97; 95% confidence interval [CI], 0.89–1.06), GU toxicity (OR, 0.97; 95% CI, 0.91–1.03), erectile dysfunction (OR, 1.06; 95% CI, 0.99–1.11), and IPSS (–0.11; 95% CI, –0.41–0.20). Also, no statistically significant association was found between these variables and time as a categorical variable. GU toxicity was associated with IPSS resolution (OR, 1.16; 95% CI, 1.09–1.24). Posttreatment IPSS was associated with pretreatment IPSS (0.52; 95% CI, 0.25–0.79).Conclusions: No accumulation of high-grade toxicity over time could be established for a group of patients treated with EBRT and PDR brachytherapy for prostate cancer, probably because high-grade late toxicity resolves with time. Also, differences in IPSS values among patients are smaller after treatment than before treatment.

CHOD/BVAM Chemotherapy and Whole-Brain Radiotherapy for Newly Diagnosed Primary Central Nervous System Lymphoma - Corrected Proof

2010-08-27

Purpose: To assess the efficacy and toxicity of chemotherapy consisting of cyclophosphamide, doxorubicin (Adriamycin), vincristine, and dexamethasone (CHOD) plus bis-chloronitrosourea (BCNU), cytosine arabinoside, and methotrexate (BVAM) followed by whole-brain irradiation (WBRT) for patients with primary central nervous system lymphoma (PCNSL).Methods and Materials: Patients 70 years old and younger with newly diagnosed, biopsy-proven PCNSL received one cycle of CHOD followed by two cycles of BVAM. Patients then received WBRT, 30.6 Gy, if a complete response was evoked, or 50.4 Gy if the response was less than complete; both doses were given in 1.8-Gy daily fractions. The primary efficacy endpoint was 1-year survival.Results: Thirty-six patients (19 men, 17 women) enrolled between 1995 and 2000. Median age was 60.5 years (range, 34 to 69 years). Thirty (83%) patients had baseline Eastern Cooperative Oncology Group performance scores of 0 to 1. All 36 patients were eligible for survival and response evaluations. Median time to progression was 12.3 months, and median survival was 18.5 months. The percentages of patients alive at 1, 2, and 3 years were 64%, 36%, and 33%, respectively. The best response was complete response in 10 patients and immediate progression in 7 patients. Ten (28%) patients had at least one grade 3 or higher neurologic toxicity.Conclusions: This regimen did improve the survival of PCNSL patients but also caused substantial toxicity. The improvement in survival is less than that reported with high-dose methotrexate-based therapies.

Distribution of Prostate Sentinel Nodes: A SPECT-Derived Anatomic Atlas - Corrected Proof

2010-08-26

Purpose: The randomized Radiation Therapy Oncology Group 94-13 trial revealed that coverage of the pelvic lymph nodes in high-risk prostate cancer confers an advantage (progression-free survival and biochemical failure) in patients with ≥15% risk of lymph node involvement. To facilitate an improved definition of the adjuvant target volume, precise knowledge regarding the location of the relevant lymph nodes is necessary. Therefore, we generated a three-dimensional sentinel lymph node atlas.Methods and Materials: In 61 patients with high-risk prostate cancer, a three-dimensional visualization of sentinel lymph nodes was performed using a single photon emission computed tomography system after transrectal intraprostatic injection of 150 to 362 (median 295) mega becquerel (MBq) 99mTechnetium-nanocolloid (1.5–3h after injection) followed by an anatomic functional image fusion.Results: In all, 324 sentinel nodes in 59 of 61 patients (96.7%) were detected, with 0 to 13 nodes per patient (median 5, mean 5.3). The anatomic distribution of the sentinel nodes was as follows: external iliac 34.3%, internal iliac 17.9%, common iliac 12.7%, sacral 8.6%, perirectal 6.2%, left paraaortic 5.3%, right paraaortic 5.3%, seminal vesicle lymphatic plexus 3.1%, deep inguinal 1.5%, superior rectal 1.2%, internal pudendal 1.2%, perivesical 0.9%, inferior rectal 0.9%, retroaortic 0.3%, superficial inguinal 0.3%, and periprostatic 0.3%.Conclusions: The distribution of sentinel nodes as detected by single photon emission computed tomography imaging correlates well with the distribution determined by intraoperative gamma probe detection. A lower detection rate of sentinels in close proximity to the bladder and seminal vesicles is probably caused by the radionuclide accumulation in the bladder. In regard to intensity-modulated radiotherapy techniques, the presented anatomic atlas may allow optimized target volume definitions.

A Randomized Trial (Irish Clinical Oncology Research Group 97-01) Comparing Short Versus Protracted Neoadjuvant Hormonal Therapy Before Radiotherapy for Localized Prostate Cancer - Corrected Proof

2010-08-26

Purpose: To examine the long-term outcomes of a randomized trial comparing short (4 months; Arm 1) and long (8 months; Arm 2) neoadjuvant hormonal therapy before radiotherapy for localized prostate cancer.Methods and Materials: Between 1997 and 2001, 276 patients were enrolled and the data from 261 were analyzed. The stratification risk factors were prostate-specific antigen level >20 ng/mL, Gleason score ≥7, and Stage T3 or more. The intermediate-risk stratum had one factor and the high-risk stratum had two or more. Staging was done from the bone scan and computed tomography findings. The primary endpoint was biochemical failure-free survival.Results: The median follow-up was 102 months. The overall survival, biochemical failure-free survival. and prostate cancer-specific survival did not differ significantly between the two treatment arms, overall or at 5 years. The cumulative probability of overall survival at 5 years was 90% (range, 87–92%) in Arm 1 and 83% (range, 80–86%) in Arm 2. The biochemical failure-free survival rate at 5 years was 66% (range, 62–71%) in Arm 1 and 63% (range, 58–67%) in Arm 2.Conclusion: No statistically significant difference was found in biochemical failure-free survival between 4 months and 8 months of neoadjuvant hormonal therapy before radiotherapy for localized prostate cancer.

Association of P53 and ATM Polymorphisms with Risk of Radiation-Induced Pneumonitis in Lung Cancer Patients Treated with Radiotherapy - Corrected Proof

2010-08-23

Purpose: Radiation-induced pneumonitis (RP) is the most common dose-limiting complication in lung cancer patients treated with radiotherapy. Accumulating evidence indicates that P53 and the ataxia telangiectasia-mutated protein (ATM)—dependent signaling response cascade play a crucial role in radiation-induced diseases. Consistent with this, our previous study showed that a functional genetic ATM polymorphism was associated with increased RP risk.Methods and Materials: To evaluate the role of genetic P53 polymorphism in RP, we analyzed the P53 Arg72Pro polymorphism in a cohort including 253 lung cancer patients receiving thoracic irradiation.Results: We found that the P53 72Arg/Arg genotype was associated with increased RP risk compared with the 72Pro/Pro genotype. Furthermore, the P53 Arg72Pro and ATM –111G>A polymorphisms display an additive combination effect in intensifying the risk of developing RP. The cross-validation test showed that 63.2% of RP cases can be identified by P53 and ATM genotypes.Conclusions: These results indicate that genetic polymorphisms in the ATM-P53 pathway influence susceptibility to RP and genotyping P53 and ATM polymorphisms might help to identify patients susceptible to developing RP when receiving radiotherapy.

Timing of Radiotherapy and Outcome in Patients Receiving Adjuvant Endocrine Therapy - Corrected Proof

2010-08-23

Purpose: To evaluate the association between the interval from breast-conserving surgery (BCS) to radiotherapy (RT) and the clinical outcome among patients treated with adjuvant endocrine therapy.Patients and Methods: Patient information was obtained from three International Breast Cancer Study Group trials. The analysis was restricted to 964 patients treated with BCS and adjuvant endocrine therapy. The patients were divided into two groups according to the median number of days between BCS and RT and into four groups according to the quartile of time between BCS and RT. The endpoints were the interval to local recurrence, disease-free survival, and overall survival. Proportional hazards regression analysis was used to perform comparisons after adjustment for baseline factors.Results: The median interval between BCS and RT was 77 days. RT timing was significantly associated with age, menopausal status, and estrogen receptor status. After adjustment for these factors, no significant effect of a RT delay ≤20 weeks was found. The adjusted hazard ratio for RT within 77 days vs. after 77 days was 0.94 (95% confidence interval [CI], 0.47–1.87) for the interval to local recurrence, 1.05 (95% CI, 0.82–1.34) for disease-free survival, and 1.07 (95% CI, 0.77–1.49) for overall survival. For the interval to local recurrence the adjusted hazard ratio for ≤48, 49–77, and 78–112 days was 0.90 (95% CI, 0.34–2.37), 0.86 (95% CI, 0.33–2.25), and 0.89 (95% CI, 0.33–2.41), respectively, relative to ≥113 days.Conclusion: A RT delay of ≤20 weeks was significantly associated with baseline factors such as age, menopausal status, and estrogen-receptor status. After adjustment for these factors, the timing of RT was not significantly associated with the interval to local recurrence, disease-free survival, or overall survival.

Post Treatment With an FGF Chimeric Growth Factor Enhances Epithelial Cell Proliferation to Improve Recovery From Radiation-Induced Intestinal Damage - Corrected Proof

2010-08-23

Purpose: A fibroblast growth factor (FGF) 1–FGF2 chimera (FGFC) was created previously and showed greater structural stability than FGF1. This chimera was capable of stimulating epithelial cell proliferation much more strongly than FGF1 or FGF2 even without heparin. Therefore FGFC was expected to have greater biologic activity in vivo. This study evaluated and compared the protective activity of FGFC and FGF1 against radiation-induced intestinal injuries.Methods and Materials: We administered FGFC and FGF1 intraperitoneally to BALB/c mice 24 h before or after total-body irradiation (TBI). The numbers of surviving crypts were determined 3.5 days after TBI with gamma rays at doses ranging from 8 to 12 Gy.Results: The effect of FGFC was equal to or slightly superior to FGF1 with heparin. However, FGFC was significantly more effective in promoting crypt survival than FGF1 (p < 0.01) when 10 μg of each FGF was administered without heparin before irradiation. In addition, FGFC was significantly more effective at promoting crypt survival (p < 0.05) than FGF1 even when administered without heparin at 24 h after TBI at 10, 11, or 12 Gy. We found that FGFC post treatment significantly promoted 5-bromo-2′-deoxyuridine incorporation into crypts and increased crypt depth, resulting in more epithelial differentiation. However, the number of apoptotic cells in FGFC-treated mice decreased to almost the same level as that in FGF1-treated mice.Conclusions: These findings suggest that FGFC strongly enhanced radioprotection with the induction of epithelial proliferation without exogenous heparin after irradiation and is useful in clinical applications for both the prevention and post treatment of radiation injuries.

p53-Dependent Adaptive Responses in Human Cells Exposed to Space Radiations - Corrected Proof

2010-08-23

Purpose: It has been reported that priming irradiation or conditioning irradiation with a low dose of X-rays in the range of 0.02–0.1 Gy induces a p53-dependent adaptive response in mammalian cells. The aim of the present study was to clarify the effect of space radiations on the adaptive response.Methods and Materials: Two human lymphoblastoid cell lines were used; one cell line bears a wild-type p53 (wtp53) gene, and another cell line bears a mutated p53 (mp53) gene. The cells were frozen during transportation on the space shuttle and while in orbit in the International Space Station freezer for 133 days between November 15, 2008 and March 29, 2009. After the frozen samples were returned to Earth, the cells were cultured for 6 h and then exposed to a challenging X-ray-irradiation (2 Gy). Cellular sensitivity, apoptosis, and chromosome aberrations were scored using dye-exclusion assays, Hoechst33342 staining assays, and chromosomal banding techniques, respectively.Results: In cells exposed to space radiations, adaptive responses such as the induction of radioresistance and the depression of radiation-induced apoptosis and chromosome aberrations were observed in wtp53 cells but not in mp53 cells.Conclusion: These results have confirmed the hypothesis that p53-dependent adaptive responses are apparently induced by space radiations within a specific range of low doses. The cells exhibited this effect owing to space radiations exposure, even though the doses in space were very low.

Assessment of Out-of-Field Doses in Radiotherapy of Brain Lesions in Children - Corrected Proof

Michael L. Taylor, Tomas Kron, Rick D. Franich — 2010-08-23

Purpose: To characterize the out-of-field doses in pediatric radiotherapy and to identify simple methods by which out-of-field dose might be minimized, with a view to reducing the risk of secondary cancers.Methods and Materials: With the aim of characterizing the peripheral doses under different treatment conditions, the dose measurements in an anthropomorphic child phantom were taken in various organs and critical structures outside the primary field using thermoluminescent dosimetry. The doses from a Varian 600C and Varian Trilogy linear accelerator, both at 6 MV, were investigated.Results: Larger field sizes have been shown to result in greater peripheral doses close to the primary beam, with the difference becoming less significant at large distances, indicating that most of out-of-field doses result from head leakage and collimator scatter >40 cm from the primary field. The use of lead shields has been shown to reduce the absorbed dose resulting from leakage. Aligning the craniocaudal axis of the patient with the x-plane of the collimator resulted in a dose reduction of 40%, for both machines. Out-of-field doses from the Varian Trilogy were shown to be approximately 40% greater than those from the 600C linear accelerator, despite being operated at the same energy.Conclusion: Out-of-field doses to pediatric patients can be minimized by using simple treatment options, such as using the single-energy mode linear accelerator rather than the multimode, orienting the couch and collimator such that the patient lies along the x-plane and avoiding fields directed along the trunk of the body.

Characterizing Interfraction Variations and Their Dosimetric Effects in Prostate Cancer Radiotherapy - Corrected Proof

2010-08-23

Purpose: To quantitatively characterize the interfraction variations and their dosimetric effects in radiotherapy for prostate cancer.Methods and Materials: A total of 486 daily computed tomography (CT) sets acquired for 20 prostate cancer patients treated with daily CT-guided repositioning using a linear accelerator and CT-on-rail combination were analyzed. The prostate, rectum, and bladder, delineated on each daily CT data set, were compared with those from the planning CT scan. Several quantities, including Dice's coefficient and the maximal overlapping rate, were used to characterize the interfraction variations. The delivered dose was reconstructed by applying the original plan to the daily CT scan with consideration of proper repositioning.Results: The mean prostate Dice's coefficient and maximal overlapping rate after bony registration was 69.7% ± 13.8% (standard deviation) and 85.6% ± 7.8% (standard deviation), respectively. The daily delivered dose distributions were generally inferior to the planned dose distribution for target coverage and/or normal structure sparing. For example, for approximately 5% of the treatment fractions, the prostate volume receiving 100% of the prescription dose decreased dramatically (15–20%) compared with its planned value. The magnitudes of the interfraction variations and their dosimetric effects indicated that, statistically, current standard repositioning using prostate alignment might be adequate for two-thirds of the fractions, but for the rest of the fractions, better on-line correction strategies, such as on-line replanning, are needed.Conclusion: Different adaptive correction schemes for prostatic interfraction changes can be used according to the anatomic changes, as quantified by the organ displacement and deformation parameters. On-line replanning is needed for approximately one-third of the treatment fractions.

Chest Wall Ewing Sarcoma Family of Tumors: Long-Term Outcomes - Corrected Proof

2010-08-23

Purpose: To review the 40-year University of Florida experience treating Ewing sarcoma family of tumors of the chest wall.Methods and Materials: Thirty-nine patients were treated from 1966 to 2006. Of the patients, 22 were treated with radiotherapy (RT) alone, and 17 patients were treated with surgery with or without RT. Of 9 patients with metastatic disease, 8 were treated with RT alone. The risk profiles of each group were otherwise similar. The median age was 16.6 years, and the most frequent primary site was the rib (n = 17). The median potential follow-up was 19.2 years.Results: The 5-year actuarial overall survival (OS), cause-specific survival (CSS), and local control (LC) rates were 34%, 34%, and 72%, respectively. For the nonmetastatic subset (n = 30), the 5-year OS, CSS, and LC rates were 44%, 44%, and 79%, respectively. LC was not statistically significantly different between patients treated with RT alone (61%) vs. surgery + RT (75%). None of the 4 patients treated with surgery alone experienced local failure. No patient or treatment variable was significantly associated with local failure. Of the patients, 26% experienced Common Toxicity Criteria (CTC) Grade 3+ toxicity, including 2 pulmonary deaths. Modern intensive systemic therapy helped increase the 5-year CSS from 7% to 49% in patients treated after 1984 (p = 0.03).Conclusions: This is the largest single-institution series describing the treatment of chest wall Ewing tumors. Despite improvements in survival, obtaining local control is challenging and often accompanied by morbidity. Effort should be focused on identifying tumors amenable to combined-modality local therapy and to improving RT techniques.

Impact of the Radiation Boost on Outcomes After Breast-Conserving Surgery and Radiation - Corrected Proof

2010-08-23

Purpose: We examined the impact of radiation tumor bed boost parameters in early-stage breast cancer on local control and cosmetic outcomes.Methods and Materials: A total of 3,186 women underwent postlumpectomy whole-breast radiation with a tumor bed boost for Tis to T2 breast cancer from 1970 to 2008. Boost parameters analyzed included size, energy, dose, and technique. Endpoints were local control, cosmesis, and fibrosis. The Kaplan–Meier method was used to estimate actuarial incidence, and a Cox proportional hazard model was used to determine independent predictors of outcomes on multivariate analysis (MVA). The median follow-up was 78 months (range, 1–305 months).Results: The crude cosmetic results were excellent in 54%, good in 41%, and fair/poor in 5% of patients. The 10-year estimate of an excellent cosmesis was 66%. On MVA, independent predictors for excellent cosmesis were use of electron boost, lower electron energy, adjuvant systemic therapy, and whole-breast IMRT. Fibrosis was reported in 8.4% of patients. The actuarial incidence of fibrosis was 11% at 5 years and 17% at 10 years. On MVA, independent predictors of fibrosis were larger cup size and higher boost energy. The 10-year actuarial local failure was 6.3%. There was no significant difference in local control by boost method, cut-out size, dose, or energy.Conclusions: Likelihood of excellent cosmesis or fibrosis are associated with boost technique, electron energy, and cup size. However, because of high local control and rare incidence of fair/poor cosmesis with a boost, the anatomy of the patient and tumor cavity should ultimately determine the necessary boost parameters.

Does the Addition of Involved Field Radiotherapy to High-Dose Chemotherapy and Stem Cell Transplantation Improve Outcomes for Patients with Relapsed/Refractory Hodgkin Lymphoma? - Corrected Proof

Shannon Kahn, Christopher Flowers, Zhiheng Xu, Natia Esiashvili — 2010-08-23

Purpose: To evaluate the value of adding involved field radiotherapy (IFRT) to patients with relapsed/refractory Hodgkin lymphoma (HL) undergoing high-dose chemotherapy (HDCT) and stem cell transplantation (SCT).Methods and Materials: Ninety-two patients with relapsed/refractory HL undergoing HDCT and SCT from 1995 to 2008 were analyzed in a case-control design. Forty-six HL patients treated with IFRT within 2 months of SCT were matched to 46 HL patients who did not receive IFRT based on age, stage at relapse, timing of relapse, histology, and year of SCT. All were evaluated for response, survival, and toxicity with a median followup of 63.5 months.Results: There was a trend for better disease control in patients receiving IFRT. Specifically, 10/46 IFRT patients (22%) relapsed/progressed after SCT compared with 17/46 control patients (37%). Of the failures after IFRT, 70% were inside the radiation field, all in sites of bulky disease. In patients with nonbulky disease, IFRT also resulted in significantly improved outcomes (failure rate 6% vs. 33%, respectively). When stratified by disease bulk, the use of IFRT was found to significantly improve DFS (p = 0.032), but did not affect OS. In addition, IFRT and nonbulky disease were found to be positive prognostic indicators for DFS with hazard ratios of 0.357 (p = 0.032) and 0.383 (p = 0.034), respectively. Grade IV/V toxicities were significantly higher in the IFRT vs. non-IFRT group (28% vs. 2%; p < 0.001), observed only in patients receiving a busulfan-based conditioning regimen.Conclusion: Patients with refractory or relapsed HL undergoing HDCT and SCT have a high risk of relapse in sites of prior disease involvement, especially in sites of bulky disease. The use of IFRT is associated with a lower risk of disease progression in these sites; however bulky disease sites are still difficult to control. Toxicity risk is significant, particularly when busulfan-based conditioning is combined with IFRT, and alternative chemotherapy conditioning regimens should be considered.

Outcomes of Postoperative Simultaneous Modulated Accelerated Radiotherapy for Head-and-Neck Squamous Cell Carcinoma - Corrected Proof

2010-08-23

Purpose: To evaluate the treatment efficacy and toxicity of postoperative simultaneous modulated accelerated radiotherapy (SMART) for patients with head-and-neck squamous cell carcinoma (HNSCC).Methods and Materials: Between February 2003 and September 2008, 51 patients with histologically confirmed HNSCC received postoperative intensity-modulated radiotherapy (N = 33) or helical tomotherapy (N = 18) using SMART after curative surgical resection. The sites included were the oral cavity (OC), oropharynx (OP), larynx, and hypopharynx in 23, 20, 5, and 3 patients, respectively.Results: The median follow-up duration of all patients and surviving patients were 32 (range, 5–78 months) and 39 months (range, 9–77 months), respectively. The 3-year overall survival, cause-specific survival, disease-free survival, locoregional recurrence-free survival (LRRFS), and distant metastasis-free survival (DMFS) in all patients were 71%, 77%, 75%, 85%, and 82%, respectively. Although no significant difference in 3-year LRRFS were found between OC (82%) and OP (82%) carcinomas, the 3-year DMFS was worse in cases of OC (66%) carcinoma compared with OP carcinoma (95%; p = 0.0414). Acute Grade 3 dermatitis, mucositis, and esophagitis occurred in 10%, 10%, and 2% of patients, respectively. At the last follow-up, Grade 3 xerostomia was documented in 10% of the patients. Young age (≤40 years) (p < 0.001) and OC carcinoma primary (p = 0.0142) were poor risk factors on univariate analysis for DMFS.Conclusion: Postoperative SMART was observed to be effective and safe in patients with HNSCC.

Outcomes After Accelerated Partial Breast Irradiation in Patients with ASTRO Consensus Statement Cautionary Features - Corrected Proof

2010-08-23

Purpose: To evaluate outcomes among women with American Society for Radiation Oncology (ASTRO) consensus statement cautionary features treated with brachytherapy-based accelerated partial breast irradiation (APBI).Methods and Materials: Between March 2001 and June 2006, 322 consecutive patients were treated with high-dose-rate (HDR) APBI at the University of Wisconsin. A total of 136 patients were identified who met the ASTRO cautionary criteria. Thirty-eight (27.9%) patients possessed multiple cautionary factors. All patients received 32 to 34 Gy in 8 to 10 twice-daily fractions using multicatheter (93.4%) or Mammosite balloon (6.6%) brachytherapy.Results: With a median follow-up of 60 months, there were 5 ipsilateral breast tumor recurrences (IBTR), three local, and two loco-regional. The 5-year actuarial rate of IBTR was 4.8% ± 4.1%. The 5-year disease-free survival was 89.6%, with a cause-specific survival and overall survival of 97.6% and 95.3%, respectively. There were no IBTRs among 32 patients with ductal carcinoma in situ (DCIS) vs. 6.1% for patients with invasive carcinoma (p = 0.24). Among 104 patients with Stage I or II invasive carcinoma, the IBTR rate for patients considered cautionary because of age alone was 0% vs. 12.7% in those deemed cautionary due to histopathologic factors (p = 0.018).Conclusions: Overall, we observed few local recurrences among patients with cautionary features. Women with DCIS and patients 50 to 59 years of age with Stage I/II disease who otherwise meet the criteria for suitability appear to be at a low risk of IBTR. Patients with tumor-related cautionary features will benefit from careful patient selection.

Favorable Prognosis in Patients with High-Grade Glioma with Radiation Necrosis: The University of Colorado Reoperation Series - Corrected Proof

2010-08-23

Purpose: To analyze the pathology, outcomes, and prognostic factors in patients with high-grade glioma undergoing reoperation after radiotherapy (RT).Methods and Materials: Fifty-one patients with World Health Organization Grade 3–4 glioma underwent reoperation after prior RT. The median dose of prior RT was 60 Gy, and 84% received chemotherapy as part of their initial treatment. Estimation of the percentage of necrosis and recurrent tumor in each reoperation specimen was performed. Pathology was classified as RT necrosis if ≥80% of the specimen was necrotic and as tumor recurrence if ≥20% was tumor. Predictors of survival were analyzed using log–rank comparisons and Cox proportional hazards regression.Results: The median interval between the completion of RT and reoperation was 6.7 months (range, 1–59 months). Pathologic analysis showed RT necrosis in 27% and recurrence in 73% of cases. Thirteen patients required a reoperation for uncontrolled symptoms. Among them, 1 patient (8%) had pathology showing RT necrosis, and 12 (92%) had tumor recurrence. Median survival after reoperation was longer for patients with RT necrosis (21.8 months vs. 7.0 months, p = 0.047). In 7 patients with Grade 4 tumors treated with temozolomide-based chemoradiation with RT necrosis, median survival from diagnosis and reoperation were 30.2 months and 21.8 months, respectively.Conclusions: Patients with RT necrosis at reoperation have improved survival compared with patients with tumor recurrence. Future efforts to intensify local therapy and increase local tumor control in patients with high-grade glioma seem warranted.

Potential Benefits of Scanned Intensity-Modulated Proton Therapy Versus Advanced Photon Therapy with Regard to Sparing of the Salivary Glands in Oropharyngeal Cancer - Corrected Proof

2010-08-23

Purpose: To test the hypothesis that scanned intensity-modulated proton therapy (IMPT) results in a significant dose reduction to the parotid and submandibular glands as compared with intensity-modulated radiotherapy with photons (IMRT) and three-dimensional conformal radiotherapy (3D-CRT) for oropharyngeal cancer. In addition, we investigated whether the achieved dose reductions would theoretically translate into a reduction of salivary dysfunction and xerostomia.Methods and Materials: Ten patients with N0 oropharyngeal carcinoma were used. The intensity-modulated plans delivered simultaneously 70 Gy to the boost planning target volume (PTV2) and 54 Gy to the elective nodal areas (PTV1). The 3D-CRT technique delivered sequentially 70 Gy and 46 Gy to PTV2 and PTV1, respectively. Normal tissue complication probabilities were calculated for salivary dysfunction and xerostomia.Results: Planning target volume coverage results were similar for IMPT and IMRT. Intensity-modulated proton therapy clearly improved the conformity. The 3D-CRT results were inferior to these results. The mean dose to the parotid glands by 3D-CRT (50.8 Gy), IMRT (25.5 Gy), and IMPT (16.8 Gy) differed significantly. For the submandibular glands no significant differences between IMRT and IMPT were found. The dose reductions obtained with IMPT theoretically translated into a significant reduction in normal tissue complication probability.Conclusion: Compared with IMRT and 3D-CRT, IMPT improved sparing of the organs at risk, while keeping similar target coverage results. The dose reductions obtained with IMPT vs. IMRT and 3D-CRT varied widely per individual patient. Intensity-modulated proton therapy theoretically translated into a clinical benefit for most cases, but this requires clinical validation.

Quantification of the Relative Biological Effectiveness for Ion Beam Radiotherapy: Direct Experimental Comparison of Proton and Carbon Ion Beams and a Novel Approach for Treatment Planning - Corrected Proof

2010-08-23

Purpose: To present the first direct experimental in vitro comparison of the biological effectiveness of range-equivalent protons and carbon ion beams for Chinese hamster ovary cells exposed in a three-dimensional phantom using a pencil beam scanning technique and to compare the experimental data with a novel biophysical model.Methods and Materials: Cell survival was measured in the phantom after irradiation with two opposing fields, thus mimicking the typical patient treatment scenario. The novel biophysical model represents a substantial extension of the local effect model, previously used for treatment planning in carbon ion therapy for more than 400 patients, and potentially can be used to predict effectiveness of all ion species relevant for radiotherapy. A key feature of the new approach is the more sophisticated consideration of spatially correlated damage induced by ion irradiation.Results: The experimental data obtained for Chinese hamster ovary cells clearly demonstrate that higher cell killing is achieved in the target region with carbon ions as compared with protons when the effects in the entrance channel are comparable. The model predictions demonstrate agreement with these experimental data and with data obtained with helium ions under similar conditions. Good agreement is also achieved with relative biological effectiveness values reported in the literature for other cell lines for monoenergetic proton, helium, and carbon ions.Conclusion: Both the experimental data and the new modeling approach are supportive of the advantages of carbon ions as compared with protons for treatment-like field configurations. Because the model predicts the effectiveness for several ion species with similar accuracy, it represents a powerful tool for further optimization and utilization of the potential of ion beams in tumor therapy.

Dose–Volume Comparison of Proton Radiotherapy and Stereotactic Body Radiotherapy for Non-Small-Cell Lung Cancer - Corrected Proof

2010-08-23

Purpose: This study designed photon and proton treatment plans for patients treated with hypofractionated proton radiotherapy (PT) at the Southern Tohoku Proton Therapy Center (STPTC). We then calculated dosimetric parameters and compared results with simulated treatment plans for stereotactic body radiotherapy (SBRT), using dose--volume histograms to clearly explain differences in dose distributions between PT and SBRT.Methods and Materials: Twenty-one patients with stage I non-small-cell lung cancer (stage IA, n = 15 patients; stage IB, n = 6 patients) were studied. All tumors were located in the peripheral lung, and total dose was 66 Gray equivalents (GyE) (6.6 GyE/fraction). For treatment planning, beam incidence for proton beam technique was restricted to two to three directions for PT, and seven or eight noncoplanar beams were manually selected for SBRT to achieve optimal planning target volume (PTV) coverage and minimal dose to organs at risk.Results: Regarding lung tissues, mean dose, V5, V10, V13, V15, and V20 values were 4.6 Gy, 13.2%, 11.4%, 10.6%, 10.1%, and 9.1%, respectively, for PT, whereas those values were 7.8 Gy, 32.0%, 21.8%, 17.4%, 15.3%, and 11.4%, respectively, for SBRT with a prescribed dose of 66 Gy. Pearson product moment correlation coefficients between PTV and dose--volume parameters of V5, V10, V15, and V20 were 0.45, 0.52, 0.58, and 0.63, respectively, for PT, compared to 0.52, 0.45, 0.71, and 0.74, respectively, for SBRT.Conclusions: Correlations between dose--volume parameters of the lung and PTV were observed and may indicate that PT is more advantageous than SBRT when treating a tumor with a relatively large PTV or several tumors.

Grade 3/4 Dermatitis in Head and Neck Cancer Patients Treated with Concurrent Cetuximab and IMRT - Corrected Proof

2010-08-23

Purpose: To assess the rate of serious (>Grade 2, CTCAE 3.0) dermatitis in our head-and-neck cancer (HNC) patients undergoing simultaneous integrated boost intensity-modulated radiotherapy with concomitant cetuximab (SIB-IMRT-cetuximab). We hypothesized a positive association between the radiation dose to the skin and the degree of dermatitis in patients receiving cetuximab.Methods and Materials: Between April 2006 and December 2009, 99 HNC patients underwent SIB-IMRT-cetuximab. In 69/99 (70%), systemic treatment consisted of concomitant cetuximab only, whereas 30 (30%) were switched from concomitant cisplatin to concomitant cetuximab. Treatment-related dermatitis was prospectively monitored. Ninety-nine patients treated with four to seven concomitant cycles of cisplatin only served as an internal control group. The radiation dose delivered to the skin was measured and related to dermal reactions.Results: Grade 3/4 dermatitis developed in 34% of the cetuximab cohort, which was substantially higher than in the control cohort (3%, p < 0.01). No cases of skin necrosis or other fatal events related to cetuximab have occurred so far. A significantly larger mean skin area was found exposed to high radiation doses in patients with severe cetuximab-related dermatitis, compared with those without (p < 0.01).Conclusion: Concomitant cetuximab resulted in a ∼10-fold increase in the rate of severe transient dermatitis compared with the use of concomitant cisplatin. We found a positive association between the incidence of Grade 3/4 dermatitis and the radiation dose delivered to the skin in patients receiving cetuximab.

Preoperative Chemoradiotherapy (CRT) Followed by Laparoscopic Surgery for Rectal Cancer: Predictors of the Tumor Response and the Long-Term Oncologic Outcomes - Corrected Proof

Jong Hoon Lee, Sung Hwan Kim, Jun-Gi Kim, Hyun Min Cho, Byoung Yong Shim — 2010-08-23

Purpose: We have evaluated the predictors of a tumor response to chemoradiotherapy (CRT) and the long-term oncologic outcomes of preoperative CRT and laparoscopic surgery for patients who suffer from rectal cancer.Methods and Materials: The study involved 274 patients with locally advanced rectal cancer and who had been treated with preoperative CRT and curative laparoscopic total mesorectal excision between January 2003 and January 2009. We assessed the long-term oncologic outcomes, in terms of recurrence and survival, of the treated patients.Results: Forty-two (15.3%) of the 274 patients had complete pathologic responses (pCR). The pre-CRT carcinoembryonic antigen level was the only significant predictor of a pCR on the multivariate analysis (p = 0.01). The overall survival at 5 years was 73.1%, with a mean survival period of 59.7 months (95% CI, 57.1–62.3). The disease-free survival at 5 years was 67.3% with a mean survival period of 54.7 months (95% CI, 51.7–57.8). The pCR group had a higher rate of overall survival at 5 years than did the non-pCR group, and the difference was significant (86.0% vs. 71.2%; hazard ratio = 0.87; 95% CI, 0.78–0.96; p = 0.03). The cumulative incidences of local and distant recurrences at 5 years were 5.8% and 28.3%, respectively. A total of 84.5% (234 of 274) of the patients had their anal sphincters preserved. Grade 3 or 4 acute and long-term toxic effects occurred in 22.2% and 8.4% of the patients, respectively.Conclusion: Preoperative CRT and laparoscopic surgery seems safe and feasible with favorable long-term outcomes and a high rate of sphincter preservation for the patients with low-lying tumors of the rectum.

Failure Rates and Patterns of Recurrence in Patients with Resected N1 Non–Small-Cell Lung Cancer - Corrected Proof

2010-08-23

Purpose: To examine the local and distant recurrence rates and patterns of failure in patients undergoing potentially curative resection of N1 non–small-cell lung cancer.Methods and Materials: The study included 60 consecutive unirradiated patients treated from 2000 to 2006. Median follow-up was 30 months. Failure rates were calculated by the Kaplan-Meier method. A univariate Cox proportional hazard model was used to assess factors associated with recurrence.Results: Local and distant failure rates (as the first site of failure) at 2, 3, and 5 years were 33%, 33%, and 46%; and 26%, 26%, and 32%, respectively. The most common site of local failure was in the mediastinum; 12 of 18 local recurrences would have been included within proposed postoperative radiotherapy fields. Patients who received chemotherapy were found to be at increased risk of local failure, whereas those who underwent pneumonectomy or who had more positive nodes had significantly increased risks of distant failure.Conclusions: Patients with resected non–small-cell lung cancer who have N1 disease are at substantial risk of local recurrence as the first site of relapse, which is greater than the risk of distant failure. The role of postoperative radiotherapy in such patients should be revisited in the era of adjuvant chemotherapy.

Effect of Breathing Motion on Radiotherapy Dose Accumulation in the Abdomen Using Deformable Registration - Corrected Proof

2010-08-23

Purpose: To investigate the effect of breathing motion and dose accumulation on the planned radiotherapy dose to liver tumors and normal tissues using deformable image registration.Methods and Materials: Twenty-one free-breathing stereotactic liver cancer radiotherapy patients, planned on static exhale computed tomography (CT) for 27–60 Gy in six fractions, were included. A biomechanical model–based deformable image registration algorithm retrospectively deformed each exhale CT to inhale CT. This deformation map was combined with exhale and inhale dose grids from the treatment planning system to accumulate dose over the breathing cycle. Accumulation was also investigated using a simple rigid liver-to-liver registration. Changes to tumor and normal tissue dose were quantified.Results: Relative to static plans, mean dose change (range) after deformable dose accumulation (as % of prescription dose) was −1 (−14 to 8) to minimum tumor, −4 (−15 to 0) to maximum bowel, −4 (−25 to 1) to maximum duodenum, 2 (−1 to 9) to maximum esophagus, −2 (−13 to 4) to maximum stomach, 0 (−3 to 4) to mean liver, and −1 (−5 to 1) and −2 (−7 to 1) to mean left and right kidneys. Compared to deformable registration, rigid modeling had changes up to 8% to minimum tumor and 7% to maximum normal tissues.Conclusion: Deformable registration and dose accumulation revealed potentially significant dose changes to either a tumor or normal tissue in the majority of cases as a result of breathing motion. These changes may not be accurately accounted for with rigid motion.

Integrating Epidermal Growth Factor Receptor Assay with Clinical Parameters Improves Risk Classification for Relapse and Survival in Head-and-Neck Squamous Cell Carcinoma - Corrected Proof

2010-08-23

Purpose: Epidermal growth factor receptor (EGFR) overexpression has been consistently found to be an independent predictor of local-regional relapse (LRR) after radiotherapy. We assessed the extent by which it can refine risk classification for overall survival (OS) and LRR in patients with head-and-neck squamous cell carcinoma (HNSCC).Methods and Materials: EGFR expression in locally advanced HNSCC was measured by immunohistochemistry in a series of patients randomized to receive accelerated or conventional radiation regimens in a Phase III trial. Subsequently, data of the two series were pooled (N = 533) for conducting a recursive partitioning analysis that incorporated clinical parameters (e.g., performance status, primary site, T and N categories) and four molecular markers (EGFR, p53, Ki-67, and microvessel density).Results: This study confirmed that patients with higher than median levels of tumor EGFR expression had a lower OS (relative risk [RR]: 1.90, p = 0.0010) and a higher LRR (RR: 1.91, p = 0.0163). Of the four markers analyzed, only EGFR was found to contribute to refining classification of patients into three risk classes with distinct OS and LRR outcomes. The addition of EGFR to three clinical parameters could identify patients having up to a fivefold difference in the risk of LRR.Conclusions: Adding pretreatment EGFR expression data to known robust clinical prognostic variables improved the estimation of the probability for OS and LRR after radiotherapy. Its use for stratifying or selecting patients with defined tumor feature and pattern of relapse for enrollment into clinical trials testing specific therapeutic strategy warrants further investigation.

Role of Peroxiredoxin I in Rectal Cancer and Related to p53 Status - Corrected Proof

2010-08-23

Background: Neoadjuvant chemoradiotherapy is widely accepted for the treatment of localized rectal cancer. Although peroxiredoxin I (PrxI) and p53 have been implicated in carcinogenesis and cancer treatment, the role of PrxI and its interaction with p53 in the prognosis and treatment response of rectal cancer remain relatively unstudied.Methods and Materials: In the present study, we examined the levels of PrxI and p53 in rectal cancer patients using membrane arrays and compared them with normal population samples. To demonstrate the biologic changes after manipulation of PrxI expression, we established stable transfectants of HCT-116 (wild-type p53) and HT-29 (mutant p53) cells with a PrxI silencing vector. The predictive capacities of PrxI and p53 were also assessed by relating the immunohistochemical staining of a retrospective series of rectal cancer cases to the clinical outcome.Results: The membrane array and immunochemical staining data showed that PrxI, but not p53, was significantly associated with the tumor burden. Our immunochemistry findings further indicated that PrxI positivity was linked to a poor response to neoadjuvant therapy and worse survival. In cellular and animal experiments, the inhibition of PrxI significantly decreased tumor growth and sensitized the tumor to irradiation, as indicated by a lower capacity to scavenge reactive oxygen species and more extensive DNA damage. The p53 status might have contributed to the difference between HCT-116 and HT-29 after knockdown of PrxI.Conclusion: According to our data, the level of PrxI combined with the p53 status is relevant to the prognosis and the treatment response. We suggested that PrxI might be a new biomarker for rectal cancer.

Association between Genetic Polymorphisms in the XRCC1, XRCC3, XPD, GSTM1, GSTT1, MSH2, MLH1, MSH3, and MGMT Genes and Radiosensitivity in Breast Cancer Patients - Corrected Proof

2010-08-13

Purpose: Clinical radiosensitivity varies considerably among patients, and radiation-induced side effects developing in normal tissue can be therapy limiting. Some single nucleotide polymorphisms (SNPs) have been shown to correlate with hypersensitivity to radiotherapy. We conducted a prospective study of 87 female patients with breast cancer who received radiotherapy after breast surgery. We evaluated the association between acute skin reaction following radiotherapy and 11 genetic polymorphisms in DNA repair genes: XRCC1 (Arg399Gln and Arg194Trp), XRCC3 (Thr241Met), XPD (Asp312Asn and Lys751Gln), MSH2 (gIVS12-6T>C), MLH1 (Ile219Val), MSH3 (Ala1045Thr), MGMT (Leu84Phe), and in damage-detoxification GSTM1 and GSTT1 genes (allele deletion).Methods and Materials: Individual genetic polymorphisms were determined by polymerase chain reaction and single nucleotide primer extension for single nucleotide polymorphisms or by a multiplex polymerase chain reaction assay for deletion polymorphisms. The development of severe acute skin reaction (moist desquamation or interruption of radiotherapy due to toxicity) associated with genetic polymorphisms was modeled using Cox proportional hazards, accounting for cumulative biologically effective radiation dose.Results: Radiosensitivity developed in eight patients and was increased in carriers of variants XRCC3-241Met allele (hazard ratio [HR] unquantifiably high), MSH2 gIVS12-6nt-C allele (HR = 53.36; 95% confidence intervals [95% CI], 3.56–798.98), and MSH3-1045Ala allele (HR unquantifiably high). Carriers of XRCC1-Arg194Trp variant allele in combination with XRCC1-Arg399Gln wild-type allele had a significant risk of radiosensitivity (HR = 38.26; 95% CI, 1.19–1232.52).Conclusions: To our knowledge, this is the first report to find an association between MSH2 and MSH3 genetic variants and the development of radiosensitivity in breast cancer patients. Our findings suggest the hypothesis that mismatch repair mechanisms may be involved in cellular response to radiotherapy. Genetic polymorphisms may be promising candidates for predicting acute radiosensitivity, but further studies are necessary to confirm our findings.

Clinical Outcomes of Intensity-Modulated Pelvic Radiation Therapy for Carcinoma of the Cervix - Corrected Proof

2010-08-13

Purpose: To evaluate disease outcomes and toxicity in cervical cancer patients treated with pelvic intensity-modulated radiation therapy (IMRT).Methods and Materials: We included all patients with Stage I–IVA cervical carcinoma treated with IMRT at three different institutions from 2000–2007. Patients treated with extended field or conventional techniques were excluded. Intensity-modulated radiation therapy plans were designed to deliver 45 Gy in 1.8-Gy daily fractions to the planning target volume while minimizing dose to the bowel, bladder, and rectum. Toxicity was graded according to the Radiation Therapy Oncology Group system. Overall survival and disease-free survival were estimated by use of the Kaplan-Meier method. Pelvic failure, distant failure, and late toxicity were estimated by use of cumulative incidence functions.Results: The study included 111 patients. Of these, 22 were treated with postoperative IMRT, 8 with IMRT followed by intracavitary brachytherapy and adjuvant hysterectomy, and 81 with IMRT followed by planned intracavitary brachytherapy. Of the patients, 63 had Stage I–IIA disease and 48 had Stage IIB–IVA disease. The median follow-up time was 27 months. The 3-year overall survival rate and the disease-free survival rate were 78% (95% confidence interval [CI], 68–88%) and 69% (95% CI, 59–81%), respectively. The 3-year pelvic failure rate and the distant failure rate were 14% (95% CI, 6–22%) and 17% (95% CI, 8–25%), respectively. Estimates of acute and late Grade 3 toxicity or higher were 2% (95% CI, 0–7%) and 7% (95% CI, 2–13%), respectively.Conclusions: Intensity-modulated radiation therapy is associated with low toxicity and favorable outcomes, supporting its safety and efficacy for cervical cancer. Prospective clinical trials are needed to evaluate the comparative efficacy of IMRT vs. conventional techniques.

Development of a Porcine Delayed Wound-Healing Model and Its Use in Testing a Novel Cell-Based Therapy - Corrected Proof

2010-08-13

Purpose: A delayed full-thickness wound-healing model was developed and used for examining the capacity of adipose-derived stem cells (ASCs), either alone or in platelet-rich fibrin gels, to promote healing.Methods and Materials: Four pigs received electron beam radiation to the dorsal skin surface. Five weeks after radiation, subcutaneous fat was harvested from nonirradiated areas and processed to yield ASCs. Two weeks later, 28 to 30 full-thickness 1.5-cm2 wounds were made in irradiated and nonirradiated skin. Wounds were treated with either saline solution, ASCs in saline solution, platelet-rich plasma (PRP) fibrin gel, ASCs in PRP, or non-autologous green fluorescence protein–labeled ASCs.Results: The single radiation dose produced a significant loss of dermal microvasculature density (75%) by 7 weeks. There was a significant difference in the rate of healing between irradiated and nonirradiated skin treated with saline solution. The ASCs in PRP-treated wounds exhibited a significant 11.2% improvement in wound healing compared with saline solution. Enhancement was dependent on the combination of ASCs and PRP, because neither ASCs nor PRP alone had an effect.Conclusions: We have created a model that simulates the clinically relevant late radiation effects of delayed wound healing. Using this model, we showed that a combination of ASCs and PRP improves the healing rates of perfusion-depleted tissues, possibly through enhancing local levels of growth factors.

Cognitive Functioning After Radiotherapy or Chemoradiotherapy for Head-and-Neck Cancer - Corrected Proof

2010-08-13

Purpose: To perform a comprehensive cognitive function (CF) assessment in patients who were relapse free after curative intent radiotherapy (RT) or chemoradiotherapy for squamous cell carcinoma of the head and neck.Methods and Materials: Patients underwent neuropsychological tests to assess their objective CF; completed questionnaires to assess subjective CF, quality of life, and affect; and underwent blood tests to assess hematologic, biochemical, endocrine, and cytokine status. Retrospectively, the dosimetry of incidental radiation to the brain was determined for all patients, and the dose intensity of cisplatin was determined in those who had undergone chemoradiotherapy.Results: A total of 10 patients were enrolled (5 treated with radiotherapy only and 5 with radiotherapy and cisplatin). The mean time from the end of treatment was 20 months (range, 9–41). All patients were able to complete the assessment protocol. Of the 10 patients, 9 had impaired objective CF, with memory the most severely affected. The severity of memory impairment correlated significantly with the radiation dose to the temporal lobes, and impaired dexterity correlated significantly with the radiation dose to the cerebellum, suggesting that these deficits might be treatment related. Patients receiving cisplatin appeared to have poorer objective CF than patients receiving only RT, although this difference did not achieve statistical significance, likely owing to the small sample size. Consistent with the published data, objective CF did not correlate with subjective CF or quality of life. No association was found between objective CF and patients' affect, hematologic, biochemical, endocrine, and cytokine status.Conclusion: Neuropsychological testing is feasible in squamous cell carcinoma of the head-and-neck survivors. The findings were suggestive of treatment-related cognitive dysfunction. These results warrant additional investigation.

Health-Related Quality of Life After Single-Fraction High-Dose-Rate Brachytherapy and Hypofractionated External Beam Radiotherapy for Prostate Cancer - Corrected Proof

2010-08-13

Purpose: To investigate the change in health-related quality of life for men after high-dose-rate brachytherapy and external beam radiotherapy for prostate cancer and the factors associated with this change.Methods and Materials: Eligible patients had clinically localized intermediate-risk prostate cancer. The patients received high-dose-rate brachytherapy as a single 15-Gy implant, followed by external beam radiotherapy to 37.5 Gy in 15 fractions. The patients were monitored prospectively for toxicity (Common Terminology Criteria for Adverse Events, version 3.0) and health-related quality of life (Expanded Prostate Cancer Index Composite [EPIC]). The proportion of patients developing a clinically significant difference in the EPIC domain score (minimally important difference of >0.5 standard deviation) was determined and correlated with the baseline clinical and dosimetric factors. The study accrued 125 patients, with a median follow-up of 24 months.Results: By 24 months, 23% had Grade 2 urinary toxicity and only 5% had Grade 2 bowel toxicity, with no Grade 3 toxicity. The proportion of patients reporting a significant decrease in EPIC urinary, bowel, sexual, and hormonal domain scores was 53%, 51%, 45%, and 40% at 12 months and 57%, 65%, 51%, and 30% at 24 months, respectively. The proportion with a >1 standard deviation decrease in the EPIC urinary, bowel, sexual, and hormonal domain scores was 38%, 36%, 24%, and 20% at 12 months and 46%, 48%, 19%, and 8% at 24 months, respectively. On multivariate analysis, the dose to 10% of the urethra was associated with a decreasing EPIC urinary domain score (p = .0089) and, less strongly (p = .0312) with a decreasing hormonal domain score. No association was found between the prostate volume, bladder dose, or high-dose volume and urinary health-related quality of life. A high baseline International Index of Erectile Function score was associated (p = .0019) with a decreasing sexual domain score. The optimal maximal dose to 10% of the urethra cutpoint for urinary health-related quality of life was 120% of the prescription dose.Conclusion: EPIC was a more sensitive tool for detecting the effects on function and bother than were the generic toxicity scales. The urethral dose had the strongest association with a deteriorating urinary quality of life.

Potential of adaptive radiotherapy to escalate the radiation dose in combined radiochemotherapy for locally advanced non–small cell lung cancer - Corrected Proof

2010-08-13

Purpose: To evaluate the potential of adaptive radiotherapy (ART) for advanced-stage non–small cell lung cancer (NSCLC) in terms of lung sparing and dose escalation.Methods and Materials: In 13 patients with locally advanced NSCLC, weekly CT images were acquired during radio- (n = 1) or radiochemotherapy (n = 12) for simulation of ART. Three-dimensional (3D) conformal treatment plans were generated: conventionally fractionated doses of 66 Gy were prescribed to the planning target volume without elective lymph node irradiation (Plan_3D). Using a surface-based algorithm of deformable image registration, accumulated doses were calculated in the CT images acquired during the treatment course (Plan_4D). Field sizes were adapted to tumor shrinkage once in week 3 or 5 and twice in weeks 3 and 5.Results: A continuous tumor regression of 1.2% per day resulted in a residual gross tumor volume (GTV) of 49% ± 15% after six weeks of treatment. No systematic differences between Plan_3D and Plan_4D were observed regarding doses to the GTV, lung, and spinal cord. Plan adaptation to tumor shrinkage resulted in significantly decreased lung doses without compromising GTV coverage: single-plan adaptation in Week 3 or 5 and twice-plan adaptation in Weeks 3 and 5 reduced the mean lung dose by 5.0% ± 4.4%, 5.6% ± 2.9% and 7.9% ± 4.8%, respectively. This lung sparing with twice ART allowed an iso–mean lung dose escalation of the GTV dose from 66.8 Gy ± 0.8 Gy to 73.6 Gy ± 3.8 Gy.Conclusions: Adaptation of radiotherapy to continuous tumor shrinkage during the treatment course reduced doses to the lung, allowed significant dose escalation and has the potential of increased local control.