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

Phase II Trial of Combined High-Dose-Rate Brachytherapy and External Beam Radiotherapy for Adenocarcinoma of the Prostate: Preliminary Results of RTOG 0321 - Corrected Proof

2010-03-08

Purpose: To estimate the rate of late Grade 3 or greater genitourinary (GU) and gastrointestinal (GI) adverse events (AEs) after treatment with external beam radiotherapy and prostate high-dose-rate (HDR) brachytherapy.Methods and Materials: Each participating institution submitted computed tomography-based HDR brachytherapy dosimetry data electronically for credentialing and for each study patient. Patients with locally confined Stage T1c-T3b prostate cancer were eligible for the present study. All patients were treated with 45 Gy in 25 fractions using external beam radiotherapy and one HDR implant delivering 19 Gy in two fractions. All AEs were graded according to the Common Terminology Criteria for Adverse Events, version 3.0. Late GU/GI AEs were defined as those occurring >9 months from the start of the protocol treatment, in patients with ≥18 months of potential follow-up.Results: A total of 129 patients from 14 institutions were enrolled in the present study. Of the 129 patients, 125 were eligible, and AE data were available for 112 patients at analysis. The pretreatment characteristics of the patients were as follows: Stage T1c-T2c, 91%; Stage T3a-T3b, 9%; prostate-specific antigen level ≤10 ng/mL, 70%; prostate-specific antigen level >10 but ≤20 ng/mL, 30%; and Gleason score 2–6, 10%; Gleason score 7, 72%; and Gleason score 8–10, 18%. At a median follow-up of 29.6 months, three acute and four late Grade 3 GU/GI AEs were reported. The estimated rate of late Grade 3-5 GU and GI AEs at 18 months was 2.56%.Conclusion: This is the first prospective, multi-institutional trial of computed tomography-based HDR brachytherapy and external beam radiotherapy. The technique and doses used in the present study resulted in acceptable levels of AEs.

Concurrent Chemoradiotherapy With Paclitaxel And Nedaplatin Followed By Consolidation Chemotherapy In Locally Advanced Squamous Cell Carcinoma of the Uterine Cervix: Preliminary Results of a Phase II Study - Corrected Proof

Mei-Qin Zhang, Su-Ping Liu, Xiang-E. Wang — 2010-03-08

Purpose: To evaluate the efficacy and toxicities of concurrent chemoradiotherapy (CCRT) and consolidation chemotherapy in patients with locally advanced squamous cell cervical carcinoma.Methods and Materials: Patients with LASCC (FIGO Stage IIB–IIIB) were treated with pelvic external beam radiotherapy (45 Gy for Stage IIB and 50 Gy for Stage III) and high-dose-rate intracavitary brachytherapy (50 Gy for Stage IIB and 35 Gy for Stage III). The cumulative dose at point A was 50 Gy for Stage IIB and 65 Gy for Stage III. Concurrent chemotherapy with paclitaxel (35 mg/m2) and nedaplatin (20 mg/m2) was given every week for 6 weeks. Consolidation chemotherapy with paclitaxel (135 mg/m2) and nedaplatin (60 mg/m2) was administered every 3 weeks for 4 cycles.Results: All patients completed CCRT, and 28 of 34 patients completed consolidation chemotherapy. The complete response rate was 88% (95% CI, 73–96%). The most common Grade 3 or higher toxicities were leukopenia/neutropenia (10.9% of the cycles). During a median follow up of 23 months (range, 14–30 months), 5 patients had locoregional failure and 1 patient had distant metastasis. The estimated 2-year progression-free survival and overall survival were 82% (95% CI, 68–95%) and 93% (95% CI, 83–100%), respectively. Grade 3 late complications occurred in 3 patients (9%).Conclusions: CCRT with paclitaxel and nedaplatin followed by consolidation chemotherapy is well tolerated and effective in patients with locally advanced squamous cell cervical carcinoma. Further randomized trials of comparing this regimen with the standard treatment are worth while.

Brachytherapy in the Treatment of Cholangiocarcinoma - Corrected Proof

Eric T. Shinohara, Mengye Guo, Nandita Mitra, James M. Metz — 2010-03-08

Purpose: To examine the role of brachytherapy in the treatment of cholangiocarcinomas in a relatively large group of patients.Methods and Materials: Using the Surveillance, Epidemiology and End Results database, a total of 193 patients with cholangiocarcinoma treated with brachytherapy were identified for the period 1988–2003. The primary analysis compared patients treated with brachytherapy (with or without external-beam radiation) with those who did not receive radiation. To try to account for confounding variables, propensity score and sensitivity analyses were used.Results: There was a significant difference between patients who received radiation (n = 193) and those who did not (n = 6859) with regard to surgery (p < 0.0001), race (p < 0.0001), stage (p < 0.0001), and year of diagnosis (p <0.0001). Median survival for patients treated with brachytherapy was 11 months (95% confidence interval [CI] 9–13 months), compared with 4 months for patients who received no radiation (p < 0.0001). On multivariable analysis (hazard ratio [95% CI]) brachytherapy (0.79 [0.66–0.95]), surgery (0.50 [0.46–0.53]), year of diagnosis (1998–2003: 0.66 [0.60–0.73]; 1993–1997: (0.96 [0.89–1.03; NS], baseline 1988–1992), and extrahepatic disease (0.84 [0.79–0.89]) were associated with better overall survival.Conclusions: To the authors' knowledge, this is the largest dataset reported for the treatment of cholangiocarcinomas with brachytherapy. The results of this retrospective analysis suggest that brachytherapy may improve overall survival. However, because of the limitations of the Surveillance, Epidemiology and End Results database, these results should be interpreted cautiously, and future prospective studies are needed.

RapidArc Radiation Therapy: First Year Experience at The University of Alabama at Birmingham - Corrected Proof

Richard A. Popple, John B. Fiveash, Ivan A. Brezovich, James A. Bonner — 2010-03-08

Purpose: To evaluate treatment planning and delivery for patients treated during our initial year of experience with RapidArc™ radiation therapy.Methods and Materials: RapidArc was used to treat 52 patients at The University of Alabama at Birmingham between May 2008 and April 2009. A single ionization chamber phantom with film and a two-dimensional ionization chamber array were used for quality assurance measurements. Of the 52 patients, 44 had a static gantry dynamic multileaf collimated (SG-DMLC) IMRT treatment plan, seven of which had quality assurance (QA) measurements.Results: The mean difference between ionization chamber measurement and calculation was 1.2% ± 0.9% (1 standard deviation). For film, the mean fraction of pixels with γ > 1 (3%/3 mm criterion) was 4.6% and for the two-dimensional chamber array was 1.4%. For the seven corresponding SG-DMLC plans, the results were similar. Differences in important dosimetric indicators were typically within 1% relative to SG-DMLC. The volume of nontarget tissue that received >20 Gy was less for RapidArc compared with SG-DMLC, whereas the volume that received more than 10 Gy was larger. The mean difference between the measured and planned leaf positions and the monitor units obtained from machine log files was 0.0 ± 0.5 mm and 0.4 ± 0.3 MU, respectively. Mean delivery times were 1.5 ± 0.2 and 3.3 ± 0.4 min for one- and two-arc plans, respectively. On average, SG-DMLC delivery took 4.4 min longer.Conclusions: RapidArc plans have quality comparable to our standard SG-DMLC IMRT technique, and are delivered with similar accuracy in shorter time.

Treatment-related Pneumonitis and Acute Esophagitis in Non–small-cell Lung Cancer Patients Treated with Chemotherapy and Helical Tomotherapy - Corrected Proof

2010-03-08

Purpose: To assess clinical outcomes and complications in patients with non–small-cell lung cancer (NSCLC) treated with helical tomotherapy (HT) with or without chemotherapy.Methods and Materials: Data from 37 NSCLC patients treated between January 2007 and August 2008 were analyzed retrospectively. Twenty-eight patients had Stage III disease. Concurrent and neoadjuvant chemotherapy was given to 24 and 14 patients, respectively. Radiotherapy was delivered to a total dose of 60–70.4 Gy at 2.0–2.4 Gy per fraction to the gross tumor volume and 50–64 Gy at 1.8–2.0 Gy per fraction to the planning target volume.Results: With a median follow-up of 18 months (range, 6–27 months), 2-year local control and overall survival rates were 63% and 56% for all 37 patients, respectively, and were 78% and 75% for the patients with Stage III disease who received concurrent chemoradiotherapy alone. Acute esophagitis and treatment-related pneumonitis (TRP) ≥Grade 3 occurred in 5 and 7 patients, respectively. Four patients died of treatment-related death (TRD) after HT. In univariate analysis, poor performance status, total lung V5, contralateral lung (CL) V5, and V10 were associated with TRD. Only CL V5 remained significant in the multivariate analysis (p = 0.029).Conclusions: HT with chemotherapy has shown promising clinical outcomes, esophagitis, and TRPs. However, HT has produced a somewhat high rate of fatal pulmonary complications. Our data suggest that CL V5 should be considered and kept as low as possible (<60%) in addition to the conventional dosimetric factors.

Whole Neuraxis Irradiation to Address Central Nervous System Relapse in High-Risk Neuroblastoma - Corrected Proof

2010-03-08

Background: As systemic control of high-risk neuroblastoma (NB) has improved, relapse in the central nervous system (CNS) is an increasingly recognized entity that carries a grim prognosis. This study describes the use of craniospinal irradiation (CSI) for CNS relapse and compares outcomes to patients who received focal radiotherapy (RT).Methods: A retrospective query identified 29 children with NB treated at Memorial Sloan-Kettering Cancer Center since 1987 who received RT for CNS relapse. At CNS relapse, 16 patients received CSI (median dose, 2160cGy), and 13 received focal RT. Of those who underwent CSI, 14 (88%) received intra-Ommaya (IO) radioimmunotherapy (RIT); one patient in the non-CSI cohort received IO-RIT.Results: Patient characteristics were similar between the groups. Time to CNS relapse was 20 and 17 months for the CSI and non-CSI cohorts, respectively. At a median follow-up of 28 months, 12 patients (75%) in the CSI group are alive without CNS disease, including two patients with isolated skeletal relapse. Another patient is alive without disease after a brain relapse was retreated with RT. Three patients died—one with no NB at autopsy, one of CNS disease, and one of systemic disease. The two patients who died of NB did not receive IO-RIT. All 13 patients in the non-CSI cohort died at a median of 8.8 months.Conclusions: Low-dose CSI together with IO-RIT provides durable CNS remissions and improved survival compared with focal RT and conventional therapies. Further evaluation of long-term NB survivors after CSI is warranted to determine the treatment consequences for this cohort.

Intensity-Modulated Radiotherapy for Cervical Node Squamous Cell Carcinoma Metastases from Unknown Head-and-Neck Primary Site: M. D. Anderson Cancer Center Outcomes and Patterns of Failure - Corrected Proof

2010-03-08

Purpose: Conventional therapy for cervical node squamous cell carcinoma metastases from an unknown primary can cause considerable toxicity owing to the volume of tissues to be irradiated. In the present study, hypothesizing that using intensity-modulated radiotherapy (IMRT) would provide effective treatment with minimal toxicity, we reviewed the outcomes and patterns of failure for head-and-neck unknown primary cancer at a single tertiary cancer center.Methods and Materials: We retrospectively reviewed the records of 52 patients who had undergone IMRT for an unknown primary at M.D. Anderson Cancer Center between 1998 and 2005. The patient and treatment characteristics were extracted and the survival rates calculated using the Kaplan-Meier method.Results: Of the 52 patients, 5 presented with Stage N1, 11 with Stage N2a, 23 with Stage N2b, 6 with Stage N2c, 4 with Stage N3, and 3 with Stage Nx disease. A total of 26 patients had undergone neck dissection, 13 before and 13 after IMRT; 14 patients had undergone excisional biopsy and presented for IMRT without evidence of disease. Finally, 14 patients had received systemic chemotherapy. All patients underwent IMRT to targets on both sides of the neck and pharyngeal axis. The median follow-up time for the surviving patients was 3.7 years. The 5-year actuarial rate of primary mucosal tumor control and regional control was 98% and 94%, respectively. Only 3 patients developed distant metastasis with locoregional control. The 5-year actuarial disease-free and overall survival rate was 88% and 89%, respectively. The most severe toxicity was Grade 3 dysphagia/esophageal stricture, experienced by 2 patients.Conclusion: The results of our study have shown that IMRT can produce excellent outcomes for patients who present with cervical node squamous cell carcinoma metastases from an unknown head-and-neck primary tumor. Severe late complications were uncommon.

Interfraction and Intrafraction Changes in Amplitude of Breathing Motion in Stereotactic Liver Radiotherapy - Corrected Proof

2010-03-08

Purpose: Interfraction and intrafraction changes in amplitude of liver motion were assessed in patients with liver cancer treated with kV cone beam computed tomography (CBCT)-guided stereotactic body radiation therapy (SBRT).Methods and Materials: A total of 314 CBCTs obtained with the patient in the treatment position immediately before and after each fraction, and 29 planning 4DCTs were evaluated in 29 patients undergoing six-fraction SBRT for unresectable liver cancer, with (n = 15) and without (n = 14) abdominal compression. Offline, the CBCTs were sorted into 10 bins, based on phase of respiration. Liver motion amplitude was measured using liver-to-liver alignment from the end-exhale and end-inhale CBCT and four-dimensional CT reconstructions. Inter- and intrafraction amplitude changes were measured from the difference between the pre-SBRT CBCTs relative to the planning four-dimensional CT, and from the pre-SBRT and post-SBRT CBCTs, respectively.Results: Mean liver motion amplitude for all patients (range) was 1.8 (0.1–7.0), 8.0 (0.1–18.8), and 4.3 (0.1–12.1) mm in the mediolateral (ML), craniocaudal (CC), and anteroposterior (AP) directions, respectively. Mean absolute inter- and intrafraction liver motion amplitude changes were 1.0 (ML), 1.7 (CC), and 1.6 (AP) mm and 1.3 (ML), 1.6 (CC), and 1.9 (AP) mm, respectively. No significant correlations were found between intrafraction amplitude change and intrafraction time (range, 4:56–25:37min:sec), and between inter- and intrafraction amplitude changes and liver motion amplitude. Intraobserver reproducibility (σ, n = 29 fractions) was 1.3 (ML), 1.4 (CC), and 1.4 (AP) mm.Conclusions: For the majority of liver SBRT patients, the change in liver motion amplitude was minimal over the treatment course and showed no apparent relationships with the magnitude of liver motion and intrafraction time.

Stereotactic Body Radiotherapy for Patients with Unresectable Primary Hepatocellular Carcinoma: Dose-Volumetric Parameters Predicting the Hepatic Complication - Corrected Proof

2010-03-08

Purpose: To identify the parameters that predict hepatic toxicity and deterioration of hepatic function.Materials and Methods: A total of 47 patients with small unresectable primary hepatocellular carcinoma received hypofractionated stereotactic body radiotherapy (SBRT) using the CyberKnife. Of those, 36 patients received no other local treatments that could influence hepatic toxicity at least for 3 months after the completion of SBRT. The gross tumor volume (GTV) was 18.3 ± 15.9 cm3 (range, 3.0–81.3 cm3), and the total dose administered was 30–39 Gy (median, 36 Gy). To assess the deterioration of hepatic function, we evaluated the presence or absence of the progression of Child-Pugh class (CP class). To identify the parameters of predicting the radiation-induced hepatic toxicity and deterioration of the hepatic function, several clinical and dose-volumetric parameters were evaluated.Results: Of 36 patients, 12 (33%) developed Grade 2 or higher hepatic toxicity and 4 (11%) developed progression of CP class. The multivariate analysis showed that the only significant parameter associated with the progression of CP class was the total liver volume receiving a dose less than 18 Gy (<18 Gy).Conclusions: The progression of CP class after SBRT limits other additional local treatments and also reflects the deterioration of hepatic function. Therefore, it would be important to note that the presence or absence of the progression of CP class is a dose-limiting factor. The total liver volume receiving <18 Gy should be greater than 800 cm3 to reduce the risk of the deterioration of hepatic function.

Intraoperative Radiotherapy for Resected Pancreatic Cancer: A Multi-Institutional Retrospective Analysis of 210 Patients - Corrected Proof

2010-03-08

Purpose: To retrospectively analyze the results of intraoperative radiotherapy (IORT) with or without external beam radiotherapy (EBRT) for resected pancreatic cancer.Methods and Materials: The records of 210 patients treated with gross complete resection (R0: 147 patients; R1: 63 patients) and IORT with or without EBRT were reviewed. One hundred forty-seven patients (70.0%) were treated without EBRT and 114 patients (54.3%) were treated in conjunction with chemotherapy. The median doses of IORT and EBRT were 25 Gy (range, 20–30 Gy) and 45 Gy (range, 20–60Gy), respectively. The median follow-up of the surviving 62 patients was 26.3 months (range, 2.7–90.5 months).Results: At the time of this analysis, 150 of 210 patients (71.4%) had disease recurrences. Local failure was observed in 31 patients (14.8%), and the 2-year local control rate in all patients was 83.7%. The median survival time and the 2-year actuarial overall survival (OS) in all 210 patients were 19.1 months and 42.1%, respectively. Patients treated with IORT and chemotherapy had a significantly more favorable OS than those treated with IORT alone (p = 0.0011). On univariate analysis, chemotherapy use, degree of resection, carbohydrate antigen 19-9, and pathological N stage had a significant impact on OS and on multivariate analysis; these four factors were significant prognostic factors. Late gastrointestinal morbidity of NCI-CTC Grade 4 was observed in 7 patients (3.3%).Conclusion: IORT yields an excellent local control rate for resected pancreatic cancer with few frequencies of severe late toxicity, and IORT combined with chemotherapy confers a survival benefit compared with that of IORT alone.

A More Efficient, Radiation-Free Alternative to Systematic Chest X-Ray for the Detection of Embolized Seeds to the lung - Corrected Proof

Janelle Morrier, Mario Chrétien, André-Guy Martin, Éric Vigneault, Luc Beaulieu — 2010-03-08

Purpose: To evaluate the efficacy of a seed-migration detector and to compare its performance to fluoroscopy and postoperative chest radiographs.Methods and Materials: A gamma scintillation survey meter was converted to a seed-migration detector by adding a shield on the probe detection window. The detector response to three 125I seed activities was characterized for different source-to-detector distances in water. The detector was used to perform a chest evaluation on 737 patients at their first postoperative visit. When the detector showed positive activity, seed migration was confirmed by taking a chest radiograph and by looking at the region with fluoroscopy.Results: One hundred and three patients (14.0%) presented at least one embolized seed. This accounts for 123 of the 39,887 seeds. Eighty-seven, 12, and 4 patients had respectively one, two, and three seed embolization. Compared with the seed-migration detector, detection based on fluoroscopy would have led to 13 false-negative detections (of 103, or 12.6%), and the radiograph would have resulted in 31 or 30.1%. More important, standard chest X-ray would have required a survey and extra radiation dose to lung to 100% of the patients, rather than the 14% who required it.Conclusions: The usual recommendation to perform chest radiographs at the first follow-up visit to scan lungs for embolized seeds should be revised because of the high false-negative rate. Scintillator-based gamma counter detector provides superior detection sensitivity and should be adopted as a standard of practice. Chest X-ray could be limited to documenting cases of positive migration.

Rectal Dose–Volume Histogram Parameters Are Associated with Long-Term Patient-Reported Gastrointestinal Quality of Life After Conventional and High-Dose Radiation for Prostate Cancer: A Subgroup Analysis of a Randomized Trial - Corrected Proof

2010-03-08

Purpose: We examined whether rectal dose–volume histogram (DVH) parameters were associated with long-term patient-reported gastrointestinal (GI) quality of life (QOL) after conventional (70.2 GyE) or high-dose (79.2 GyE) radiation for prostate cancer.Methods and Materials: Of 64 men with localized prostate cancer alive with a minimum 7-year follow-up after treatment as part of a randomized trial with either 70.2 GyE or 79.2 GyE of external beam radiation at Massachusetts General Hospital, 56 men (88%) returned a QOL questionnaire, and 50 of those men had DVH information. The DVH parameters of the anterior rectal wall were correlated with patient-reported long-term GI QOL using Pearson correlation and t tests.Results: There was a trend toward an association between increased long-term GI dysfunction and higher V60 (p = 0.07), V65 (p = 0.06), V70 (p = 0.09), and V75 (p = 0.09). When dichotomized by their medians, a V60 > 54% (p = 0.04), V70 > 44% (p = 0.06), and V75 > 39% (p = 0.06) were associated with increased long-term GI dysfunction. There was no difference in long-term GI dysfunction between men on the conventional vs. high-dose arms (p = 0.49).Conclusions: Dose–volume histogram parameters of the anterior rectal wall were associated with long-term patient-reported GI QOL after prostate radiation, whereas the dose prescribed to the prostate was not, suggesting that DVH constraints, rather than total prescribed dose, may have the greatest impact on long-term bowel dysfunction, and therefore that continued dose escalation may be feasible if appropriate dose–volume constraints are met.

Patterns and Timing of Recurrence After Temozolomide-Based Chemoradiation for Glioblastoma - Corrected Proof

2010-03-08

Purpose: To determine recurrence patterns of glioblastoma treated with temozolomide-based chemoradiation.Methods: Pretreatment and serial posttreatment magnetic resonance imaging scans of 54 patients were retrospectively evaluated. Central recurrence (i.e., local progression) and the development of new (i.e., interval appearance of discrete enhancing lesion) in-field, marginal, and distant recurrences were assessed, with the pattern of recurrence of individual lesions defined relative to the 95% isodose line (D95). Distant recurrences were defined as lesions completely outside D95, marginal recurrences crossed D95, and in-field recurrences were completely inside D95.Results: At a median follow-up of 17 months, 39 of 54 (72%) patients developed recurrent glioblastoma. Among these 39 patients, central recurrence occurred in 80% (at a median of 7 months from diagnosis); new in-field recurrence developed in 33% (at a median of 14 months); marginal recurrences developed in 15% (at a median of 18 months); and distant recurrences developed in 20% (at a median of 11 months). The actuarial rates of central, new in-field, marginal, distant, and any new recurrences at 1-year were 46%, 15%, 3%, 14%, and 25% respectively, whereas at 2 years, the rates were 68%, 60%, 32%, 28%, and 66%, reflecting an increasing probability of new lesions developing at later time points. Ten patients developed subependymal recurrences, of whom 7 developed multiple subependymal lesions.Conclusions: Whereas central recurrence of glioblastoma treated with radiation and temozolomide predominates and persists over time, new in-field, marginal, and distant recurrences commonly develop, particularly at later time points in patients with longer survival.

Initial Experience with Volumetric IMRT (RapidArc) for Intracranial Stereotactic Radiosurgery - Corrected Proof

2010-03-08

Purpose: Initial experience with delivering frameless stereotactic radiotherapy (SRT) using volumetric intensity-modulated radiation therapy (IMRT) delivered with RapidArc is presented.Methods and Materials: Treatment details for 12 patients (14 targets) with a mean clinical target volume (CTV) of 12.8 ± 4.0 cm3 were examined. Dosimetric indices for conformality, homogeneity, and dose gradient were calculated and compared with published results for other frameless, intracranial SRT techniques, including CyberKnife, TomoTherapy, and static-beam IMRT. Statistics on setup and treatment times and per patient dose validations were examined.Results: Dose indices compared favorably with other techniques. Mean conformality, gradient, and homogeneity index values were 1.10 ± 0.11, 64.9 ± 14.1, 1.083 ± 0.026, respectively. Median treatment times were 4.8 ± 1.7 min.Conclusion: SRT using volumetric IMRT is a viable alternative to other techniques and enables short treatment times. This is anticipated to have a positive impact on radiobiological effect and for facilitating wider use of SRT.

Clinical Results of Image-Guided Deep Inspiration Breath Hold Breast Irradiation - Corrected Proof

2010-03-08

Purpose: To evaluate the feasibility, cardiac dose reduction, and the influence of the setup error on the delivered dose for fluoroscopy-guided deep inspiration breath hold (DIBH) irradiation using a cone-beam CT for irradiation of left-sided breast cancer patients.Methods and Materials: Nineteen patients treated according to the DIBH protocol were evaluated regarding dose to the ipsilateral breast (or thoracic wall), heart, (left ventricle [LV] and left anterior descending artery [LAD]), and lung. The DIBH treatment plan was compared to the free-breathing (FB) treatment planning and to the dose data in which setup error was taken into account (i.e., actual delivered dose).Results: The largest setup variability was observed in the direction perpendicular to the RT field (μ = –0.8 mm, Σ = 2.9 mm, σ = 2.0 mm). The mean (Dmean) and maximum (Dmax) doses of the DIBH treatment plan was significantly lower compared with the FB treatment plan for the heart (34% and 25%, p <0.001), LV (71% and 28%, p <0.001), and LAD (52% and 39.8%, p <0.001). For some patients, large differences were observed between the heart Dmax according to the DIBH treatment plan and the actual delivered dose (up to 71%), although Dmax was always smaller than the planned FB dose (mean group reduction = 29%, p <0.001).Conclusion: The image-guided DIBH treatment protocol is a feasible irradiation method with small setup variability that significantly reduces the dose to the heart, LV, and LAD.

Effect of Lumpectomy Cavity Volume Change on the Clinical Target Volume for Accelerated Partial Breast Irradiation: A Deformable Registration Study - Corrected Proof

Leonard H. Kim, Sam DeCesare, Frank Vicini, Di Yan — 2010-03-08

Purpose: Previous studies have shown that lumpectomy cavity volumes can change significantly in the weeks following surgery. The effect of this volume change on the surrounding tissue that constitutes the clinical target volume (CTV) for accelerated partial breast irradiation and boost treatment after whole breast irradiation has not been previously studied. In the present study, we used deformable registration to estimate the effect of lumpectomy cavity volume changes on the CTV for accelerated partial breast irradiation and discuss the implications for target construction.Methods and Materials: The data from 13 accelerated partial breast irradiation patients were retrospectively analyzed. Deformable registration was used to propagate contours from the initial planning computed tomography scan to a later computed tomography scan acquired at the start of treatment. The changes in cavity volume and CTV, distance between cavity and CTV contours (i.e., CTV margin), and CTV localization error after cavity registration were determined.Results: The mean ± standard deviation change in cavity volume and CTV between the two computed tomography scans was −35% ± 23% and −14% ± 12%, respectively. An increase in the cavity-to-CTV margin of 2 ± 2 mm was required to encompass the CTV, and this increase correlated with the cavity volume change. Because changes in the cavity and CTV were not identical, a localization error of 2–3 mm in the CTV center of mass occurred when the cavity was used as the reference for image guidance.Conclusion: Deformable registration suggested that CTV margins do not remain constant as the cavity volume changes. This finding has implications for planning target volume and CTV construction.

Comparison of Standardized Uptake Value–Based Positron Emission Tomography and Computed Tomography Target Volumes in Esophageal Cancer Patients Undergoing Radiotherapy - Corrected Proof

2010-03-03

Purpose: To study various standardized uptake value (SUV)-based approaches to ascertain the best strategy for delineating metabolic tumor volumes (MTV).Methods and Materials: Twenty-two consecutive previously treated esophageal cancer patients with positron emission tomography (PET) imaging and computed tomography (CT)-based radiotherapy plans were studied. At the level of the tumor epicenter, MTVs were delineated at 11 different thresholds: SUV ≥2, ≥2.5, ≥3, ≥3.5 (SUVn); ≥40%, ≥45%, and ≥50% of the maximum (SUVn%); and mean liver SUV + 1, 2, 3, and 4 standard deviations (SUVLnσ). The volume ratio and conformality index were determined between MTVs, and the corresponding CT/endoscopic ultrasound-based gross tumor volume (GTV) at the epicenter. Means were analyzed by one-way analysis of variance for repeated measures and further compared using a paired t test for repeated measures.Results: The mean conformality indices ranged from 0.33 to 0.48, being significantly (p < 0.05) closest to 1 at SUV2.5 (0.47 ± 0.03) and SUVL4σ (0.48 ± 0.03). The mean volume ratios ranged from 0.39 to 2.82, being significantly closest to 1 at SUV2.5 (1.18 ± 0.36) and SUVL4σ (1.09 ± 0.15). The mean value of the SUVs calculated using the SUVL4σ approach was 2.4.Conclusions: Regardless of the SUV thresholding method used (i.e., absolute or relative to liver mean), a threshold of approximately 2.5 yields the highest conformality index and best approximates the CT-based GTV at the epicenter. These findings may ultimately aid radiation oncologists in the delineation of the entire GTV in esophageal cancer patients.

Ipsilateral Irradiation for Oral and Oropharyngeal Carcinoma Treated With Primary Surgery and Postoperative Radiotherapy - Corrected Proof

2010-02-26

Purpose: The purpose was to evaluate the contralateral nodal control (CLNC) in postoperative patients with oral and oropharyngeal cancer treated with ipsilateral irradiation of the neck and primary site. Late radiation-induced morbidity was also evaluated.Methods and Materials: The study included 123 patients with well-lateralized squamous cell carcinomas treated with surgery and unilateral postoperative irradiation. Most patients had tumors of the gingiva (41%) or buccal mucosa (21%). The majority of patients underwent surgery of the ipsilateral neck (n = 102 [83%]). The N classification was N0 in 73 cases (59%), N1 or N2a in 23 (19%), and N2b in 27 cases (22%).Results: Contralateral metastases developed in 7 patients (6%). The 5-year actuarial CLNC was 92%. The number of lymph node metastases was the only significant prognostic factor with regard to CLNC. The 5-year CLNC was 99% in N0 cases, 88% in N1 or N2a cases, and 73% in N2b cases (p = 0.008). Borderline significance (p = 0.06) was found for extranodal spread. Successful salvage could be performed in 71% of patients with contralateral metastases. The prevalence of Grade 2 or higher xerostomia was 2.6% at 5 years.Conclusions: Selected patients with oral or oropharyngeal carcinoma treated with primary surgery and postoperative ipsilateral radiotherapy have a very high CLNC with a high probability of successful salvage in case of contralateral metastases. However, bilateral irradiation should be applied in case of multiple lymph node metastases in the ipsilateral neck, particularly in the presence of extranodal spread. The incidence of radiation-induced morbidity is considerably lower as observed after bilateral irradiation.

In Reply to Drs. Beal and McCormick - Corrected Proof

Leonard R. Prosnitz — 2010-02-26

To the Editor: Dr. Beal and Dr. McCormick's data are most interesting but in their own words “limited” (or as others might say, “preliminary”), based on a fairly small number of patients. In contrast, a recent review of MRI in patients with early breast cancer demonstrated that MRI detected additional disease in 16% of patients . Whether this is true for the older patient typically selected for accelerated partial-breast irradiation (APBI) remains to be determined. Whether the MRI is detecting biologically significant disease is uncertain. However, that disease is addressed by whole-breast irradiation and not by APBI. Until the Memorial Sloan-Kettering group's data are confirmed in larger studies, we still think it is prudent to perform MRI in most patients being considered for APBI.

Radiotherapy With or Without Concurrent Chemotherapy for Lymph Node Recurrence After Radical Surgery of Thoracic Esophageal Squamous Cell Carcinoma - Corrected Proof

Jin-Cheng Lu, Cheng Kong, Hua Tao — 2010-02-22

Purpose: To retrospectively compare the outcomes of patients with lymph node recurrence after radical surgery of esophageal cancer, when given radiotherapy with or without concurrent chemotherapy.Methods and Materials: Between January 1996 and December 2005, the data from 73 patients with lymph node recurrence after radical surgery of thoracic esophageal squamous cell carcinoma were retrospectively reviewed. The patients were separated into two groups: radiochemotherapy (RC, 31 patients) and radiotherapy alone (RA, 42 patients). Patients in the RC group received at least two cycles of 5-fluorouracil/cisplatin chemotherapy concurrently with radiotherapy.Results: The median duration of follow-up was 11 months (range, 2–48). The overall survival rate for all patients was 46.7% and 4.7% at 1 and 3 years, respectively. The median overall survival time was 9 months (95% confidence interval, 6.96–11.04) and 17 months (95% confidence interval, 13.61–20.39) for RA and RC groups, respectively. The survival rate at 1 and 3 years was 62.5% and 10.5% in the RC group and 33.8% and 0% in the RA group (p = .0049, log–rank test; hazard ratio for death, 0.52; 95% confidence interval, 0.30–0.92). Acute toxicities were more frequent in the RC group than in the RA group. No significant differences were found in the late toxicity profiles between the two groups.Conclusion: The results of the present retrospective analysis suggest that RC should be considered an effective and well-tolerated treatment of patients with thoracic esophageal squamous cell carcinoma and postoperative lymph node recurrence.

Alternative Dose for Choroidal Melanoma Treated with an Iodine-125 Radioactive Plaque: A Single-Institution Retrospective Study - Corrected Proof

2010-02-22

Purpose: The Collaborative Ocular Melanoma Study (COMS) established iodine-125 plaque brachytherapy as an accepted standard treatment for medium-size choroidal melanoma. In the COMS, the prescription dose was 85 Gy. This is a retrospective review of our outcomes in patients treated with lower doses than those used in the COMS.Methods and Materials: From 1990 to 2004, 62 patients were treated with iodine-125 plaque brachytherapy for choroidal melanoma. COMS eye plaques were used with dose prescribed to the apex of the tumor. The median and average dose rates at the tumor apex were 63.5 cGy/h and 62.7 cGy/h, respectively. The median and average total doses were 63.0 Gy and 62.5 Gy (range, 56–69 Gy), respectively. The median and mean durations of implant were 100.0 hours and 101.1 hours (range, 71–165 hours).Results: Median follow-up time was 58.2 months. The 5-year outcomes including overall survival, disease-free survival, cause-specific survival, local failure, secondary enucleation rate, and visual acuity (VA) <20/200 were estimated using the Kaplan-Meier method. Overall, there were 7 local failures, 4 distant failures, and 10 secondary enucleations (6 due to local failure and 4 due to treatment complications). Univariate analysis was performed to identify significant prognostic factors associated with disease-free survival (baseline VA in tumor eye, tumor shape), cause-specific survival (diabetic retinopathy), local failure (none found), secondary enucleation rate (diabetic retinopathy, basal tumor dimension) and VA <20/200 (diabetic retinopathy, tumor shape, age, retinal detachment, treatment depth, and history of vision-limiting condition).Conclusions: Our survival and local control outcomes are comparable to those of the COMS. However, VA at 5 years seems to be better. Lower doses of radiation could potentially lead to better visual outcomes.

Comparison Between High and Low Source Activity Seeds for I-125 Permanent Seed Prostate Brachytherapy - Corrected Proof

2010-02-22

Purpose: To compare low (mean 0.44, SD ± 0.0163 mCi) with high source activity (0.61 ± 0.0178 mCi) in I125 permanent seed brachytherapy regarding seed loss, dosimetric outcome, and toxicity.Methods and Materials: The study included 199 patients with prostate cancer treated by permanent seed brachytherapy alone: the first 105 with seeds of lower activity (first cohort), the following 94 with higher seed activity (second cohort). The V100, V150, V200, and D90 were analyzed on the CT scan 30 days after implantation (CTD30). The V100, V150, and D2 of the rectum were also calculated on CTD30. Seed loss was determined 30 days after implantation. Urinary toxicity was measured with the International Prostate Symptom Score (IPSS) questionnaire.Results: Lower seed activity was associated with lower V150 and V200 (p = 0.01 and p ≤ 0.001, respectively) on CTD30. More patients had a V100 <90% and D90 <140 Gy in the lower activity cohort (p = 0.098 for D90 and p = 0.029 for V100) on CTD30. There was no difference between cohorts in dose to the rectum (p = 0.325–0.516) or difference in patients' IPSS score from baseline (p = 0.0.117–0.618), although there was a trend toward more urinary toxicity at 4 and 8 months for high activity seeds. Seed loss as a percentage of implanted seeds was not different (p = 0.324).Conclusions: Higher seed activity (I125 ≥ 0.6 mCi) results in at least equal V100 and D90 on CTD30. However, dose inhomogeneity and a trend toward more urinary toxicity at 4 and 8 months after treatment may lead to a higher long-term urinary complications.

Optimization of Collimator Trajectory in Volumetric Modulated Arc Therapy: Development and Evaluation for Paraspinal SBRT - Corrected Proof

2010-02-22

Purpose: To develop a collimator trajectory optimization paradigm for volumetric modulated arc therapy (VMAT) and evaluate this technique in paraspinal stereotactic body radiation therapy (SBRT).Method and Materials: We propose a novel VMAT paradigm, Coll-VMAT, which integrates collimator rotation with synchronized gantry rotation, multileaf collimator (MLC) motion, and dose-rate modulation. At each gantry angle a principal component analysis (PCA) is applied to calculate the primary cord orientation. The collimator angle is then aligned so that MLC travel is parallel to the PCA-derived direction. An in-house VMAT optimization follows the geometry-based collimator trajectory optimization to obtain the optimal MLC position and monitor units (MU) at each gantry angle. A treatment planning study of five paraspinal SBRT patients compared Coll-VMAT to standard VMAT (fixed collimator angle) and static field IMRT plans. Plan evaluation statistics included planning target volume (PTV) V95%, PTV-D95%, cord-D05%, and total beam-on time.Results: Variation of collimator angle in Coll-VMAT plans ranges from 26° to 54°, with a median of 40°. Patient-averaged PTV V95% (94.6% Coll-VMAT vs. 92.1% VMAT and 93.3% IMRT) and D95% (22.5 Gy vs. 21.4 Gy and 22.0 Gy, respectively) are highest with Coll-VMAT, and cord D05% (9.8 Gy vs. 10.0 Gy and 11.7 Gy) is lowest. Total beam-on time with Coll-VMAT (5,164 MU) is comparable to standard VMAT (4,868 MU) and substantially lower than IMRT (13,283 MU).Conclusion: Collimator trajectory optimization-based VMAT provides an additional degree of freedom that can improve target coverage and cord sparing of paraspinal SBRT plans compared with standard VMAT and IMRT approaches.

A Simple and Effective Daily Pain Management Method for Patients Receiving Radiation Therapy for Painful Bone Metastases - Corrected Proof

2010-02-22

Purpose: The incidence of painful bone metastases increases with longer survival times. Although external beam radiation therapy (EBRT) is an effective palliative treatment, it often requires several days from the start of treatment to produce a measurable reduction in pain scores and a qualitative amelioration of patient pain levels. Meanwhile, the use of analgesics remains the best approach early on in the treatment course. We investigated the role of radiation therapists as key personnel for collecting daily pain scores to supplement assessments by physician and oncology nursing staff and manage pain more effectively during radiation treatment.Methods and Materials: Daily pain scores were obtained by the radiation therapists for 89 patients undertaking a total of 124 courses of EBRT for bone metastases and compared with pretreatment pain scores. The majority of patients (71%) were treated to 30 Gy (range, 20–37.5) in 10 fractions (range, 8–15 fractions).Results: One hundred nineteen treatment courses (96%) were completed. Pain scores declined rapidly to 37.5%, 50%, and 75% of the pretreatment levels by Days 2, 4, and 10, respectively. Pain was improved in 91% of patients with only 4% of worse pain at the end of treatment. Improved pain scores were maintained in 83% of patients at 1-month follow-up, but in 35% of them, the pain was worse than at the end of treatment.Conclusions: Collection of daily pain scores by radiation therapists was associated with an effective reduction in pain scores early on during EBRT of painful osseous metastases.

Quantitative Ultrasonic Evaluation of Radiation-Induced Late Tissue Toxicity: Pilot Study of Breast Cancer Radiotherapy - Corrected Proof

2010-02-22

Purpose: To investigate the use of advanced ultrasonic imaging to quantitatively evaluate normal-tissue toxicity in breast-cancer radiation treatment.Methods and Materials: Eighteen breast cancer patients who received radiation treatment were enrolled in an institutional review board–approved clinical study. Radiotherapy involved a radiation dose of 50.0 to 50.4 Gy delivered to the entire breast, followed by an electron boost of 10.0 to 16.0 Gy delivered to the tumor bed. Patients underwent scanning with ultrasound during follow-up, which ranged from 6 to 94 months (median, 22 months) postradiotherapy. Conventional ultrasound images and radio-frequency (RF) echo signals were acquired from treated and untreated breasts. Three ultrasound parameters, namely, skin thickness, Pearson coefficient, and spectral midband fit, were computed from RF signals to measure radiation-induced changes in dermis, hypodermis, and subcutaneous tissue, respectively. Ultrasound parameter values of the treated breast were compared with those of the untreated breast. Ultrasound findings were compared with clinical assessment using Radiation Therapy Oncology Group (RTOG) late-toxicity scores.Results: Significant changes were observed in ultrasonic parameter values of the treated vs. untreated breasts. Average skin thickness increased by 27.3%, from 2.05 ± 0.22mm to 2.61 ± 0.52mm; Pearson coefficient decreased by 31.7%, from 0.41 ± 0.07 to 0.28 ± 0.05; and midband fit increased by 94.6%, from -0.92 ± 7.35 dB to 0.87 ± 6.70 dB. Ultrasound evaluations were consistent with RTOG scores.Conclusions: Quantitative ultrasound provides a noninvasive, objective means of assessing radiation-induced changes to the skin and subcutaneous tissue. This imaging tool will become increasingly valuable as we continue to improve radiation therapy technique.

Predictive Factors of Late Radiation Fibrosis: A Prospective Study in Non–Small Cell Lung Cancer - Corrected Proof

2010-02-19

Purpose: To determine predictive factors of late radiation fibrosis (RF) after conformal radiotherapy (3D-RT) in non–small cell lung cancer (NSCLC).Methods and Materials: Ninety-six patients with Stage IA–IIIB NSCLC were included in a prospective trial. Clinical evaluation, chest X-ray, and pulmonary functional tests including diffusion parameters were performed before and 6 months after radiotherapy. An independent panel of experts prospectively analyzed RF, using Late Effects in Normal Tissues—Subjective, Objective, Management and Analytic scales classification. Logistic regression analysis was performed to identify relationships between clinical, functional, or treatment parameters and incidence of RF. Variations of circulating serum levels of pro-inflammatory (interleukin-6, tumor necrosis factor α, tumor growth factor β1) and anti-inflammatory (interleukin-10) cytokines during 3D-RT were examined to identify correlations with RF.Results: Of the 96 patients included, 72 were evaluable for RF at 6 months. Thirty-seven (51.4%) developed RF (Grade ≥1), including six severe RF (Grades 2–3; 8.3%). In univariate analysis, only poor Karnofsky Performance Status and previous acute radiation pneumonitis were associated with RF (p < 0.05). Dosimetric factors (mean lung dose, percentage of lung volume receiving more than 10, 20, 30, 40, and 50 Gy) were highly correlated with RF (p < 0.001). In multivariate analysis, previous acute radiation pneumonitis and dosimetric parameters were significantly correlated with RF occurrence. It was not significantly correlated either with cytokines at baseline or with their variation during 3D-RT.Conclusions: This study confirms the importance of dosimetric parameters to limit the risk of RF. Contrary to acute radiation pneumonitis, RF was not correlated to cytokine variations during 3D-RT.

The Association Between Biological Subtype and Isolated Regional Nodal Failure After Breast-Conserving Therapy - Corrected Proof

2010-02-19

Purpose: To evaluate the risk of isolated regional nodal failure (RNF) among women with invasive breast cancer treated with breast-conserving surgery (BCS) and radiation therapy (RT) and to determine factors, including biological subtype, associated with RNF.Methods and Materials: We retrospectively studied 1,000 consecutive women with invasive breast cancer who received breast-conserving surgery and RT from 1997 through 2002. Ninety percent of patients received adjuvant systemic therapy; none received trastuzumab. Sentinel lymph node biopsy was done in 617 patients (62%). Of patients with one to three positive nodes, 34% received regional nodal irradiation (RNI). Biological subtype classification into luminal A, luminal B, HER-2, and basal subtypes was based on estrogen receptor status–, progesterone receptor status–, and HER-2–status of the primary tumor.Results: Median follow-up was 77 months. Isolated RNF occurred in 6 patients (0.6%). On univariate analysis, biological subtype (p = 0.0002), lymph node involvement (p = 0.008), lymphovascular invasion (p = 0.02), and Grade 3 histology (p = 0.01) were associated with significantly higher RNF rates. Compared with luminal A, the HER-2 (p = 0.01) and basal (p = 0.08) subtypes were associated with higher RNF rates. The 5-year RNF rate among patients with one to three positive nodes treated with tangents alone was 2.4%; we could not identify a subset of these patients with a substantial risk of RNF.Conclusions: Isolated RNF is a rare occurrence after breast-conserving therapy. Patients with the HER-2 (not treated with trastuzumab) and basal subtypes appear to be at higher risk of developing RNF although this risk is not high enough to justify the addition of RNI. Low rates of RNF in patients with one to three positive nodes suggest that tangential RT without RNI is reasonable in most patients.

ATM Polymorphisms Are Associated With Risk of Radiation-Induced Pneumonitis - Corrected Proof

2010-02-19

Purpose: Since the ataxia telangiectasia mutated (ATM) protein plays crucial roles in repair of double-stranded DNA breaks, control of cell cycle checkpoints, and radiosensitivity, we hypothesized that variations in this gene might be associated with radiation-induced pneumonitis (RP).Methods and Materials: A total of 253 lung cancer patients receiving thoracic irradiation between 2004 and 2006 were included in this study. Common Terminology Criteria for Adverse Events version 3.0 was used to grade RP. Five haplotype-tagging single nucleotide polymorphisms (SNPs) in the ATM gene were genotyped using DNA from blood lymphocytes. Hazard ratios (HRs) and 95% confidence intervals (CIs) of RP for genotypes were computed by the Cox model, adjusted for clinical factors. The function of the ATM SNP associated with RP was examined by biochemical assays.Results: During the median 22-month follow-up, 44 (17.4%) patients developed grade ≥ 2 RP. In multivariate Cox regression models adjusted for other clinical predictors, we found two ATM variants were independently associated with increased RP risk. They were an 111G > A) polymorphism (HR, 2.49; 95% CI, 1.07–5.80) and an ATM 126713G > A polymorphism (HR, 2.47; 95% CI, 1.16–5.28). Furthermore, genotype-dependent differences in ATM expression were demonstrated both in cell lines (p < 0.001) and in individual lung tissue samples (p = 0.003), which supported the results of the association study.Conclusions: Genetic polymorphisms of ATM are significantly associated with RP risk. These variants might exert their effect through regulation of ATM expression and serve as independent biomarkers for prediction of RP in patients treated with thoracic radiotherapy.

Hypofractionated Whole-Brain Radiotherapy for Multiple Brain Metastases from Transitional Cell Carcinoma of the Bladder - Corrected Proof

Dirk Rades, Thekla Meyners, Theo Veninga, Lukas J.A. Stalpers, Steven E. Schild — 2010-02-19

Purpose: Brain metastases in bladder cancer patients are extremely rare. Most patients with multiple lesions receive longer-course whole-brain radiotherapy (WBRT) with 10 × 3 Gy/2 weeks or 20 × 2 Gy/4 weeks. Because its radiosensitivity is relatively low, metastases from bladder cancer may be treated better with hypofractionated radiotherapy. This study compared short-course hypofractionated WBRT (5 × 4 Gy/1 week) to longer-course WBRT.Methods and Materials: Data for 33 patients receiving WBRT alone for multiple brain metastases from transitional cell bladder carcinoma were retrospectively analyzed. Short-course WBRT with 5 × 4 Gy (n = 12 patients) was compared to longer-course WBRT with 10 × 3 Gy/20 × 2 Gy (n = 21 patients) for overall survival (OS) and local (intracerebral) control (LC). Five additional potential prognostic factors were investigated: age, gender, Karnofsky performance score (KPS), number of brain metastases, and extracranial metastases. The Bonferroni correction for multiple tests was used to adjust the p values derived from the multivariate analysis. p values of <0.025 were considered significant.Results: At 6 months, OS was 42% after 5 × 4 Gy and 24% after 10 × 3/20 × 2 Gy (p = 0.31). On univariate analysis, improved OS was associated with less than four brain metastases (p = 0.021) and almost associated with a lack of extracranial metastases (p = 0.057). On multivariate analysis, both factors were not significant. At 6 months, LC was 83% after 5 × 4 Gy and 27% after 10 × 3/20 × 2 Gy (p = 0.035). Improved LC was almost associated with a KPS of ≥70 (p = 0.051). On multivariate analysis, WBRT regimen was almost significant (p = 0.036). KPS showed a trend (p = 0.07).Conclusions: Short-course WBRT with 5 × 4 Gy should be seriously considered for most patients with multiple brain metastases from bladder cancer, as it resulted in improved LC.

Stereotactic, Single-Dose Irradiation of Lung Tumors: A Comparison of Absolute Dose and Dose Distribution Between Pencil Beam and Monte Carlo Algorithms Based on Actual Patient CT Scans - Corrected Proof

2010-02-19

Purpose: Dose calculation based on pencil beam (PB) algorithms has its shortcomings predicting dose in tissue heterogeneities. The aim of this study was to compare dose distributions of clinically applied non–intensity-modulated radiotherapy 15-MV plans for stereotactic body radiotherapy between voxel Monte Carlo (XVMC) calculation and PB calculation for lung lesions.Methods and Materials: To validate XVMC, one treatment plan was verified in an inhomogeneous thorax phantom with EDR2 film (Eastman Kodak, Rochester, NY). Both measured and calculated (PB and XVMC) dose distributions were compared regarding profiles and isodoses. Then, 35 lung plans originally created for clinical treatment by PB calculation with the Eclipse planning system (Varian Medical Systems, Palo Alto, CA) were recalculated by XVMC (investigational implementation in PrecisePLAN [Elekta AB, Stockholm, Sweden]). Clinically relevant dose–volume parameters for target and lung tissue were compared and analyzed statistically.Results: The XVMC calculation agreed well with film measurements (<1% difference in lateral profile), whereas the deviation between PB calculation and film measurements was up to +15%. On analysis of 35 clinical cases, the mean dose, minimal dose and coverage dose value for 95% volume of gross tumor volume were 1.14 ± 1.72 Gy, 1.68 ± 1.47 Gy, and 1.24 ± 1.04 Gy lower by XVMC compared with PB, respectively (prescription dose, 30 Gy). The volume covered by the 9 Gy isodose of lung was 2.73% ± 3.12% higher when calculated by XVMC compared with PB. The largest differences were observed for small lesions circumferentially encompassed by lung tissue.Conclusions: Pencil beam dose calculation overestimates dose to the tumor and underestimates lung volumes exposed to a given dose consistently for 15-MV photons. The degree of difference between XVMC and PB is tumor size and location dependent. Therefore XVMC calculation is helpful to further optimize treatment planning.

Clinical Toxicities and Dosimetric Parameters After Whole-Pelvis Versus Prostate-Only Intensity-Modulated Radiation Therapy for Prostate Cancer - Corrected Proof

Curtiland Deville, Stefan Both, Wei-Ting Hwang, Zelig Tochner, Neha Vapiwala — 2010-02-19

Purpose: To assess whether whole-pelvis (WP) intensity-modulated radiation therapy (IMRT) is associated with increased toxicity compared with prostate-only (PO) IMRT.Methods and Materials: We retrospectively analyzed all patients with prostate cancer undergoing definitive IMRT to 79.2 Gy with concurrent androgen deprivation at our institution from November 2005 to May 2007 with a minimum follow-up of 12 months. Thirty patients received initial WP IMRT to 45 Gy in 1.8-Gy fractions, and thirty patients received PO IMRT. Study patients underwent computed tomography simulation and treatment planning by use of predefined dose constraints. Bladder and rectal dose–volume histograms, maximum genitourinary (GU) and gastrointestinal (GI) Radiation Therapy Oncology Group toxicity grade, and late Grade 2 or greater toxicity-free survival curves were compared between the two groups by use of the Student t test, Fisher exact test, and Kaplan-Meier curve, respectively.Results: Bladder minimum dose, mean dose, median dose, volume receiving 5 Gy, volume receiving 20 Gy, volume receiving 40 Gy, and volume receiving 45 Gy and rectal minimum dose, median dose, and volume receiving 20 Gy were significantly increased in the WP group (all p values < 0.01). Maximum acute GI toxicity was limited to Grade 2 and was significantly increased in the WP group at 50% vs. 13% the PO group (p = 0.006). With a median follow-up of 24 months (range, 12–35 months), there was no difference in late GI toxicity (p = 0.884) or in acute or late GU toxicity.Conclusions: Despite dosimetric differences in the volume of bowel, bladder, and rectum irradiated in the low-dose and median-dose regions, WP IMRT results only in a clinically significant increase in acute GI toxicity, in comparison to PO IMRT, with no difference in GU or late GI toxicity.

Is Regional Lymph Node Irradiation Necessary in Stage II to III Breast Cancer Patients with Negative Pathologic Node Status After Neoadjuvant Chemotherapy? - Corrected Proof

2010-02-19

Purpose: Neoadjuvant chemotherapy (NAC) generally induces significant changes in the pathologic extent of disease. This potential down-staging challenges the standard indications of adjuvant radiation therapy. We assessed the utility of lymph node irradiation (LNI) in breast cancer (BC) patients with pathologic N0 status (pN0) after NAC and breast-conserving surgery (BCS).Methods and Materials: Among 1,054 BC patients treated with NAC in our institution between 1990 and 2004, 248 patients with clinical N0 or N1 to N2 lymph node status at diagnosis had pN0 status after NAC and BCS. Cox regression analysis was used to identify factors influencing locoregional recurrence–free survival (LRR-FS), disease-free survival (DFS), and overall survival (OS).Results: All 248 patients underwent breast irradiation, and 158 patients (63.7%) also received LNI. With a median follow-up of 88 months, the 5-year LRR-FS and OS rates were respectively 89.4% and 88.7% with LNI and 86.2% and 92% without LNI (no significant difference). Survival was poorer among patients who did not have a pathologic complete primary tumor response (hazard ratio, 3.05; 95% confidence interval, 1.17–7.99) and in patients with N1 to N2 clinical status at diagnosis (hazard ratio = 2.24; 95% confidence interval, 1.15–4.36). LNI did not significantly affect survival.Conclusions: Relative to combined breast and local lymph node irradiation, isolated breast irradiation does not appear to be associated with a higher risk of locoregional relapse or death among cN0 to cN2 breast cancer patients with pN0 status after NAC. These results need to be confirmed in a prospective study.

Does Lymphovascular Invasion Predict Regional Nodal Failure in Breast Cancer Patients with zero to three positive lymph nodes Treated with Conserving Surgery and Radiotherapy? Implications for Regional Radiation - Corrected Proof

2010-02-19

Purpose: To examine the relationship between lymphovascular invasion (LVI) and regional nodal failure (RNF) in breast cancer patients with zero to three positive nodes treated with breast-conservation therapy (BCT).Methods and Materials: The records of 1,257 breast cancer patients with zero to three positive lymph nodes were reviewed. All patients were treated with BCT at Massachusetts General Hospital from 1980 to December 2003. Lymphovascular invasion was diagnosed by hematoxylin and eosin–stained sections and in some cases supported by immunohistochemical stains. Regional nodal failure was defined as recurrence in the ipsilateral supraclavicular, axillary, or internal mammary lymph nodes. Regional nodal failure was diagnosed by clinical and/or radiologic examination.Results: The median follow-up was 8 years (range, 0.1–21 years). Lymphovascular invasion was present in 211 patients (17%). In univariate analysis, patients with LVI had a higher rate of RNF (3.32% vs. 1.15%; p = 0.02). In multivariate analysis, only tumor size, grade, and local failure were significant predictors of RNF (p = 0.049, 0.013, and 0.0001, respectively), whereas LVI did not show a significant relationship with RNF (hazard ratio = 2.07; 95% CI, 0.8–5.5; p = 0.143). The presence of LVI in the T2/3 population did not increase the risk of RNF over that for those with no LVI (p = 0.15). In addition, patients with Grade 3 tumors and positive LVI did not have a higher risk of RNF than those without LVI (p = 0.96).Conclusion: These results suggest that LVI can not be used as a sole indicator for regional nodal irradiation in breast cancer patients with zero to three positive lymph nodes treated with BCT.

Absence of Symptom and Intact Liver Function Are Positive Prognosticators for Patients Undergoing Radiotherapy for Lymph Node Metastasis From Hepatocellular Carcinoma - Corrected Proof

2010-02-19

Purpose: The positive role of radiotherapy for patients with lymph node (LN) metastasis from hepatocellular carcinoma has recently been reported. The outcome and prognostic factors for these patients were analyzed.Methods and Materials: Between May 2004 and October 2007, 38 patients with LN metastases from hepatocellular carcinoma underwent radiotherapy. The median age was 59 years (range, 42–81). The radiation dose was 35–56 Gy with a fraction size of 1.8–3 Gy, for a biologically effective dose of 43.75–67.2 Gy10 (median, 59.0). The median follow-up period was 8 months.Results: The median survival time was 10 months. On univariate analysis, Child-Pugh class B (p = .0006), distant metastasis (p = .0095), symptoms related to metastatic LNs (p <.0001), and a biologically effective dose <60 Gy10 (p = .0042) were significant prognostic factors predicting for poor overall survival. On multivariate analysis after adjustment using the Benjamini and Hochberg (false discovery rate) method, Child-Pugh class B (p = .04095) and the presence of symptoms (p = .04095) were associated with inferior overall survival. When patients were divided into three groups according to these two risk factors, the median survival for patients with no, either, or both risk factors was 20, 7, and 4 months, respectively (p <.0001).Conclusion: Patients with intact liver function and without related symptoms had the best prognosis when undergoing radiotherapy for LN metastasis from hepatocellular carcinoma.

Stereotactic Body Radiotherapy and Gemcitabine for Locally Advanced Pancreatic Cancer - Corrected Proof

2010-02-19

Purpose: Patients with nonmetastatic locally advanced unresectable pancreatic cancer have a dismal prognosis. Conventional concurrent chemoradiotherapy requires 6 weeks of daily treatment and can be arduous. We explored the safety and effectiveness of a 3-day course of hypofractionated stereotactic body radiotherapy (SBRT) followed by gemcitabine in this population.Patients and Methods: A total of 36 patients with nonmetastatic, locally advanced, unresectable pancreatic cancer with ≥12 months of follow-up were included. They received three fractions of 8, 10, or 12 Gy (total dose, 24–36 Gy) of SBRT according to the tumor location in relation to the stomach and duodenum, using fiducial-based respiratory motion tracking on a robotic radiosurgery system. The patients were then offered gemcitabine for 6 months or until tolerance or disease progression.Results: With an overall median follow-up of 24 months (range, 12–33), the local control rate was 78%, the median overall survival time was 14.3 months, the median carbohydrate antigen 19-9–determined progression-free survival time was 7.9 months, and the median computed tomography-determined progression-free survival time was 9.6 months. Of the 36 patients, 28 (78%) eventually developed distant metastases. Six patients (17%) were free of progression at the last follow-up visit (range, 13–30 months) as determined by normalized tumor markers with stable computed tomography findings. Nine Grade 2 (25%) and five Grade 3 (14%) toxicities attributable to SBRT occurred.Conclusion: Hypofractionated SBRT can be delivered quickly and effectively in patients with nonmetastatic, locally advanced, unresectable pancreatic cancer with acceptable side effects and minimal interference with gemcitabine chemotherapy.

PSA Decrease during Combined-modality Radiotherapy Predicts for Treatment Outcome - Corrected Proof

2010-02-19

Purpose: Prostate-specific antigen (PSA) is the well-used marker in the diagnosis, prognosis, and follow-up for prostate cancer patients. Although reports have focused on the importance of pretreatment PSA levels, doubling time, and posttreatment nadirs, there is little information on the value of PSA during the course of radiotherapy.Methods and Materials: Retrospective review of PSA values obtained midway through a course of radiotherapy treatment for prostate cancer. Patients had a PSA (midPSA) measured after a course of external beam radiation (EBRT) before planned transperineal low-dose-rate brachytherapy implant (LDR).Results: A total of 717 patients were analyzed with a median follow-up of 5.8 years, all censored patients had a minimum follow-up of 2 years. A total of 277 patients had low-risk disease, 267 patients had intermediate risk, and 173 patients had high-risk disease. Androgen blockade was used in 512 patients. A total of 653 patients had a midPSA decrease after EBRT, the median decrease was 6.2 ng/mL. Patients who had a midPSA decrease ≥25% compared with pretreatment PSA had improved overall survival of 10.0 vs. 7.4 years (p < 0.0004) and improved disease-free survival of 9.8 vs. 7.3 years (p < 0.01). When stratified by use of androgen blockade, midPSA remained significant for both androgen and non-androgen patients.Conclusions: PSA response after EBRT before brachytherapy predicts for long-term outcome; this may allow for risk stratification and intervention with higher LDR doses to improve outcomes.

Prospective Imaging Assessment of Mortality Risk After Head-and-Neck Radiotherapy - Corrected Proof

2010-02-19

Purpose: The optimal roles for imaging-based biomarkers in the management of head-and-neck cancer remain undefined. Unresolved questions include whether functional or anatomic imaging might improve mortality risk assessment for this disease. We addressed these issues in a prospective institutional trial.Methods and Materials: Ninety-eight patients with locally advanced pharyngolaryngeal squamous cell cancer were enrolled. Each underwent pre- and post-chemoradiotherapy contrast-enhanced computed tomography (CT) and 18F-fluorodeoxyglucose (FDG)-positron emission tomography (PET)/CT imaging. Imaging parameters were correlated with survival outcomes.Results: Low post-radiation primary tumor FDG avidity correlated with improved survival on multivariate analysis; so too did complete primary tumor response by CT alone. Although both imaging modalities lacked sensitivity, each had high specificity and negative predictive value for disease-specific mortality risk assessment. Kaplan-Meier estimates confirmed that both CT and FDG-PET/CT stratify patients into distinct high- and low-probability survivorship groups on the basis of primary tumor response to radiotherapy. Subset analyses demonstrated that the prognostic value for each imaging modality was primarily derived from patients at high risk for local treatment failure (human papillomavirus [HPV]-negative disease, nonoropharyngeal primary disease, or tobacco use).Conclusions: CT alone and FDG-PET/CT are potentially useful tools in head-and-neck cancer–specific mortality risk assessment after radiotherapy, particularly for selective use in cases of high-risk HPV-unrelated disease. Focus should be placed on corroboration and refinement of patient selection for imaging-based biomarkers in future studies.

Evaluation of the Effectiveness of the Stereotactic Body Frame in Reducing Respiratory Intrafractional Organ Motion using the Real-time Tumor-tracking Radiotherapy System - Corrected Proof

2010-02-19

Purpose: To evaluate the effectiveness of the stereotactic body frame (SBF), with or without a diaphragm press or a breathing cycle monitoring device (Abches), in controlling the range of lung tumor motion, by tracking the real-time position of fiducial markers.Methods and Materials: The trajectories of gold markers in the lung were tracked with the real-time tumor-tracking radiotherapy system. The SBF was used for patient immobilization and the diaphragm press and Abches were used to actively control breathing and for self-controlled respiration, respectively. Tracking was performed in five setups, with and without immobilization and respiration control. The results were evaluated using the effective range, which was defined as the range that includes 95% of all the recorded marker positions in each setup.Results: The SBF, with or without a diaphragm press or Abches, did not yield effective ranges of marker motion which were significantly different from setups that did not use these materials. The differences in the effective marker ranges in the upper lobes for all the patient setups were less than 1mm. Larger effective ranges were obtained for the markers in the middle or lower lobes.Conclusion: The effectiveness of controlling respiratory-induced organ motion by using the SBF+diaphragm press or SBF + Abches patient setups were highly dependent on the individual patient reaction to the use of these materials and the location of the markers. They may be considered for lung tumors in the lower lobes, but are not necessary for tumors in the upper lobes.

Magnetic Resonance Imaging Assessment of Squamous Cell Carcinoma of the Anal Canal Before and After Chemoradiation: Can MRI Predict for Eventual Clinical Outcome? - Corrected Proof

2010-02-19

Purpose: To describe the MRI appearances of squamous cell carcinoma of the anal canal before and after chemoradiation and to assess whether MRI features predict for clinical outcome.Methods and Materials: Thirty-five patients (15 male, 20 female; mean age 60.8 years) with histologically proven squamous cell cancer of the anal canal underwent MRI before and 6–8 weeks after definitive chemoradiation. Images were reviewed retrospectively by two radiologists in consensus blinded to clinical outcome: tumor size, signal intensity, extent, and TNM stage were recorded. Following treatment, patients were defined as responders by T and N downstaging and Response Evaluation Criteria in Solid Tumors (RECIST). Final clinical outcome was determined by imaging and case note review: patients were divided into (1) disease-free and (2) with relapse and compared using appropriate univariate methods to identify imaging predictors; statistical significance was at 5%.Results: The majority of tumors were ≤T2 (23/35; 65.7%) and N0 (21/35; 60%), mean size 3.75cm, and hyperintense (++ to +++, 24/35 patients; 68%). Following chemoradiation, there was a size reduction in all cases (mean 73.3%) and a reduction in signal intensity in 26/35 patients (74.2%). The majority of patients were classified as responders (26/35 (74.2%) patients by T and N downstaging; and 30/35 (85.7%) patients by RECIST). At a median follow-up of 33.5 months, 25 patients (71.4%) remained disease-free; 10 patients (28.6%) had locoregional or metastatic disease. Univariate analysis showed that no individual MRI features were predictive of eventual outcome.Conclusion: Early assessment of response by MRI at 6–8 weeks is unhelpful in predicting future clinical outcome.

T1N0 to T2N0 Squamous Cell Carcinoma of the Glottic Larynx Treated with Definitive Radiotherapy - Corrected Proof

2010-02-12

Purpose: To report the treatment outcomes of definitive radiotherapy (RT) for early-stage squamous cell carcinoma (SCCA) of the glottic larynx.Methods and Materials: We retrospectively reviewed the medical records of 585 patients with T1N0 to T2N0 invasive SCCA of the glottic larynx treated between 1964 and 2006 with RT alone. All patients had at least 2 years of follow-up, had histologic diagnosis of invasive SCCA, and received continuous-course RT. None of these patients received chemotherapy or had elective nodal RT. The probabilities of local control (LC), ultimate LC, ultimate LC with larynx preservation, neck control, cause-specific survival (CSS), and overall survival (OS) were calculated by the Kaplan-Meier product-limit method.Results: The median follow-up for survivors was 12 years. Five-year LC rates were as follows: T1A, 94%; T1B, 93%; T2A, 80%; and T2B, 70%. Multivariate analysis revealed that overall treatment time greater than 41 days (p = 0.001) and poorly differentiated histology (p = 0.016) adversely affected LC. Five-year rates of ultimate LC with laryngeal preservation were: T1A, 95%; T1B, 94%, T2A, 81%; and T2B, 74%. Twenty-four (4%) of 585 patients failed in the neck; only 7 neck failures (1%) were isolated. Five-year CSS and OS rates were as follows: T1A, 97% and 82%; T1B, 99% and 83%; T2A, 94% and 76%; and T2B, 90% and 78%, respectively. Ten (1.7%) patients had severe and/or fatal complications. One patient died of a radiation-induced carotid artery angiosarcoma.Conclusion: Based on our study results, RT cures a high proportion of patients with T1N0 to T2N0 glottic SCCAs and has a low rate of severe complications.

DNA Repair Alterations in Children with Pediatric Malignancies: Novel Opportunities to Identify Patients at Risk for High-Grade Toxicities - Corrected Proof

2010-02-12

Purpose: To evaluate, in a pilot study, the phosphorylated H2AX (γH2AX) foci approach for identifying patients with double-strand break (DSB) repair deficiencies, who may overreact to DNA-damaging cancer therapy.Methods and Materials: The DSB repair capacity of children with solid cancers was analyzed compared with that of age-matched control children and correlated with treatment-related normal-tissue responses (n = 47). Double-strand break repair was investigated by counting γH2AX foci in blood lymphocytes at defined time points after irradiation of blood samples.Results: Whereas all healthy control children exhibited proficient DSB repair, 3 children with tumors revealed clearly impaired DSB repair capacities, and 2 of these repair-deficient children developed life-threatening or even lethal normal-tissue toxicities. The underlying mutations affecting regulatory factors involved in DNA repair pathways were identified. Moreover, significant differences in mean DSB repair capacity were observed between children with tumors and control children, suggesting that childhood cancer is based on genetic alterations affecting DSB repair function.Conclusions: Double-strand break repair alteration in children may predispose to cancer formation and may affect children's susceptibility to normal-tissue toxicities. Phosphorylated H2AX analysis of blood samples allows one to detect DSB repair deficiencies and thus enables identification of children at risk for high-grade toxicities.

Disturbed Colonic Motility Contributes to Anorectal Symptoms and Dysfunction After Radiotherapy for Carcinoma of the Prostate - Corrected Proof

2010-02-12

Purpose: To evaluate the role of colonic motility in the pathogenesis of anorectal symptoms and dysfunction after radiotherapy (RT) for carcinoma of the prostate.Patients and Methods: Thirty-eight patients, median age 71 (range, 50–81) years with localized prostate carcinoma randomized to one of two radiation dose schedules underwent colonic transit scintigraphy and assessment of anorectal symptoms (questionnaire), anorectal function (manometry), and anal sphincteric morphology (endoanal ultrasound) before and at 1 month and 1 year after RT.Results: Whole and distal colonic transit increased 1 month after RT, with faster distal colonic transit only persisting at 1 year. Frequency and urgency of defecation, fecal incontinence, and rectal bleeding increased 1 month after RT and persisted at 1 year. Basal anal pressures remained unchanged, but progressive reductions occurred in anal squeeze pressures and responses to increased intra-abdominal pressure. Rectal compliance decreased progressively in the patients, although no changes in anorectal sensory function ensued. Radiotherapy had no effect on the morphology of the internal and external anal sphincters. Distal colonic retention was weakly related to rectal compliance at 1 month, but both faster colonic transit and reduced rectal compliance were more frequent with increased fecal urgency. At 1 year, a weak inverse relationship existed between colonic half-clearance time and frequency of defecation, although both faster whole-colonic transit and reduced rectal compliance occurred more often with increased stool frequency.Conclusion: Colonic dysmotility contributes to anorectal dysfunction after RT for carcinoma of the prostate. This has implications for improving the management of anorectal radiation sequelae.

Clinical Study of the Necessity of Replanning Before the 25th Fraction During the Course of Intensity-Modulated Radiotherapy for Patients with Nasopharyngeal Carcinoma - Corrected Proof

2010-02-08

Purpose: To quantify the target and normal structures on dose distributing variations during intensity-modulated radiotherapy (IMRT) and to assess the value of replanning for nasopharyngeal carcinoma (NPC) patients.Methods and Materials: Twenty-eight NPC patients treated with IMRT were recruited. The IMRT was delivered in 33 fractions, to 70 to 76Gy, to the gross tumor volume (GTV). Before the 25th fraction of IMRT, a new simulation computed tomography (CT) scan was acquired for all patients. According to the dose constraint criterion in the Radiation Therapy Oncology Group (RTOG) 0225 protocol, the replanning was generated on the new simulation CT. With the Quality Assessment Center of a CORVUS 6.3 treatment planning system, a phantom plan was generated for each patient by applying the beam configurations of the initial plan to the anatomy of the new simulation CT. The dose–volume histograms of the phantom plan were compared with the replanning.Results: The percentage of prescription dose delivered to the clinical target volume (CTV1) was significantly increased by 4.91% ± 10.89%, whereas the maximum dose to the spinal cord, mean dose to the left parotid, and V30 to the right parotid were significantly decreased by 5.00 ± 9.23Gy, 4.23 ± 10.03Gy, and 11.47% ± 18.89% respectively in the replanning, compared with the phantom plan (p < 0.05). Based on the dose constraint criterion in the RTOG0225 protocol, 50% of phantom plans (14/28) were out of limit for the dose to the normal critical structures, whereas no plan was out of limit in replanning (p < 0.001).Conclusion: Replanning for patients with NPC before the 25th fraction during IMRT helps to ensure adequate dose to the target volumes and safe doses to critical normal structures.

Long-Term Outcome and Toxicity of Salvage Brachytherapy for Local Failure After Initial Radiotherapy for Prostate Cancer - Corrected Proof

Ryan J. Burri, Nelson N. Stone, Pam Unger, Richard G. Stock — 2010-02-05

Purpose: To describe long-term outcomes and toxicity after salvage brachytherapy (BT) for local failure after initial radiotherapy for prostate cancer.Methods and Materials: Between 1994 and 2008, 37 men with local failure after initial prostate radiotherapy (32 external-beam radiation therapy [EBRT] and 5 BT) underwent salvage BT with 103Pd or 125I. Estimates of freedom from biochemical failure (FFbF, Phoenix definition) and cause-specific survival (CSS) were calculated using the Kaplan-Meier method. Toxicities were graded using CTCv3.0.Results: Median follow-up was 86 months (range, 2–156). The median dose to 90% of the prostate volume was 122 Gy (range, 67–166). The 10-year FFbF and CSS were 54% and 96%, respectively. On univariate analysis, prostate-specific antigen (PSA) >10 ng/mL at initial diagnosis was significantly associated with FFbF (p = 0.01), and there were trends for both age <70 years (p = 0.08) and PSA <6 ng/mL (p = 0.08) at the time of salvage BT. On multivariate analysis, only presalvage PSA <6 ng/mL (p = 0.046) was significantly associated with improved FFbF. There were three Grade 3 toxicities and one Grade 4 toxicity. Pelvic lymph node dissection before salvage BT was the only variable significantly associated with Grade ≥2 toxicity (p = 0.03).Conclusion: With a median follow-up of 86 months, salvage prostate BT was associated with a 10-year FFbF of 54% and CSS of 96%. Improved FFbF was associated with a presalvage PSA <6 ng/mL. Toxicity was worse in patients who had undergone pelvic lymph node dissection before salvage BT. Careful patient selection for salvage BT may result in improved outcomes and reduced toxicity.

Preliminary Results on Setup Precision of Prone-Lateral Patient Positioning for Whole Breast Irradiation - Corrected Proof

2010-02-05

Purpose: The aim of this study was to develop a rapid and reproducible technique for prone positioning and to compare dose–volume indices in prone and supine positions.Methods and Materials: Eighteen patients underwent computed tomography imaging for radiotherapy planning in prone and supine position. Experience was gained in the first eight patients, which lead to modifications of the Horizon prone breast board (Civco Medical Solutions, Orange City, Iowa, USA) and the patient setup technique. A unilateral breast holder (U-BH) was developed (Van de Velde, Schellebelle, Belgium) to retract the contralateral breast away from the treated breast.The technique was then applied to an additional 10 patients. The setup precision was evaluated using daily cone-beam CT.Results: Modifications to the breast board were made to secure a prone-lateral rather then a pure prone position. We evolved from a classical setup using laser marks on the patients' body to a direct breast setup using marks on the breast only. The setup precision of the direct positioning procedure with the modified breast board and the U-BH is comparable to supine setup data in the literature. Dose–volume indices for heart and lung show significantly better results for prone than for supine position, and dose homogeneity within the treated breast did not differ according to the treatment position.Conclusions: The setup precision of our prone-lateral positioning technique is comparable to supine data in literature. Our data show the advantage of prone radiotherapy to spare the lung and heart. Further research is necessary to reduce the duration of prone setup.

Concurrent Liposomal Cisplatin (Lipoplatin), 5-Fluorouracil and Radiotherapy for the Treatment of Locally Advanced Gastric Cancer: A Phase I/II Study - Corrected Proof

2010-02-05

Purpose: Liposomal drugs have a better tolerance profile and are highly accumulated in the tumor environment, properties that promise an optimal radiosensitization. We investigated the feasibility of the combination of 5-fluorouracil/lecovorin–based radio-chemotherapy with the administration of high weekly dose of a liposomal platinum formulation (Lipoplatin™).Methods and Materials: Lipoplatin was given at a dose of 120mg/m2/week, 5-fluorouracil at 400mg/m2/week (Day 1), whereas radiotherapy was given through 3.5-Gy fractions on Days 2, 3, and 4. Two groups of 6 patients received four and five consecutive cycles, respectively.Results: Minimal nephrotoxicity (18.2% Grade 1) and neutropenia (9% Grade 3) was noted. Fatigue Grade 2 appeared in 25% of cases. Abdominal discomfort was reported by 18% of patients. No liver, kidney, gastric, or intestinal severe acute or late sequellae were documented, although the median follow-up of 9 months is certainly too low to allow safe conclusions. A net improvement in the performance status (from a median of 1 to 0) was recorded 2 months after the end of therapy. The response rates assessed with computed tomography, endoscopy, and biopsies confirmed 33% (2 of 6) tumor disappearance in patients treated with four cycles, which reached 80% (4 of 5) in patients receiving five cycles.Conclusions: Lipoplatin radio-chemotherapy is feasible, with minor hematological and nonhematological toxicity. The high complete response rates obtained support the testing of Lipoplatin in the adjuvant postoperative or preoperative radio-chemotherapy setting for the treatment of gastric cancer.

Evaluation of Tumor Position and PTV Margins Using Image Guidance and Respiratory Gating - Corrected Proof

2010-02-04

Purpose: To evaluate the margins currently used to generate the planning target volume for lung tumors and to determine whether image-guided patient setup or respiratory gating is more effective in reducing uncertainties in tumor position.Methods and Materials: Lung tumors in 7 patients were contoured on serial four-dimensional computed tomography (4DCT) data sets (4–8 4DCTs/patient; 50 total) obtained throughout the course of treatment. Simulations were performed to determine the tumor position when the patient was aligned using skin marks, image-guided setup based on vertebral bodies, fiducials implanted near the tumor, and the actual tumor volume under various scenarios of respiratory gating.Results: Because of the presence of setup uncertainties, the reduction in overall margin needed to completely encompass the tumor was observed to be larger for imaged-guided patient setup than for a simple respiratory-gated treatment. Without respiratory gating and image-guided patient setup, margins ranged from 0.9 cm to 3.1 cm to completely encompass the tumor. These were reduced to 0.7–1.7 cm when image-guided patient setup was simulated and further reduced with respiratory gating.Conclusions: Our results indicate that if respiratory motion management is used, it should be used in conjunction with image-guided patient setup in order to reduce the overall treatment margin effectively.

Phase I Study of Vandetanib with Radiotherapy and Temozolomide for Newly Diagnosed Glioblastoma - Corrected Proof

2010-02-04

Purpose: Increasing evidence has suggested that angiogenesis inhibition might potentiate the effects of radiotherapy and chemotherapy in patients with glioblastoma (GBM). In addition, epidermal growth factor receptor inhibition might be of therapeutic benefit, because the epidermal growth factor receptor is upregulated in GBM and contributes to radiation resistance. We conducted a Phase I study of vandetanib, an inhibitor of vascular endothelial growth factor receptor 2 and epidermal growth factor receptor, in patients with newly diagnosed GBM combined with RT and temozolomide (TMZ).Methods and Materials: A total of 13 GBM patients were treated with vandetanib, radiotherapy, and concurrent and adjuvant TMZ, using a standard “3 + 3” dose escalation. The maximal tolerated dose was defined as the dose with <1 of 6 dose-limiting toxicities during the first 12 weeks of therapy. The eligible patients were adults with newly diagnosed GBM, Karnofsky performance status of ≥60, normal organ function, who were not taking enzyme-inducing antiepileptic drugs.Results: Of the 13 patients, 6 were treated with vandetanib at a dose of 200mg daily. Of the 6 patients, 3 developed dose-limiting toxicities within the first 12 weeks, including gastrointestinal hemorrhage and thrombocytopenia in 1 patient, neutropenia in 1 patient, and diverticulitis with gastrointestinal perforation in 1 patient. The other 7 patients were treated with 100 mg daily, with no dose-limiting toxicities observed, establishing this dose as the maximal tolerated dose combined with TMZ and RT.Conclusion: Vandetanib can be safely combined with RT and TMZ in GBM patients. A Phase II study in which patients are randomized to vandetanib 100 mg daily with RT and TMZ or RT and TMZ alone is underway.

Sexual Function after Stereotactic Body Radiotherapy for Prostate Cancer: Results of a Prospective Clinical Trial - Corrected Proof

Ellen A. Wiegner, Christopher R. King — 2010-02-04

Purpose: To study the sexual quality of life for prostate cancer patients after stereotactic body radiotherapy (SBRT).Methods and Materials: Using the Expanded Prostate Cancer Index Composite (EPIC)-validated quality-of-life questionnaire, the sexual function of 32 consecutive patients who received prostate SBRT in a prospective Phase II clinical trial were analyzed at baseline, and at median times of 4, 12, 20, and 50 months after treatment. SBRT consisted of 36.25 Gy in five fractions of 7.25 Gy using the Cyberknife. No androgen deprivation therapy was given. The use of erectile dysfunction (ED) medications was monitored. A comprehensive literature review for radiotherapy-alone modalities based on patient self-reported questionnaires served as historical comparison.Results: Median age at treatment was 67.5 years, and median follow-up was 35.5 months (minimum 12 months). The mean EPIC sexual domain summary score, sexual function score, and sexual bother score decreased by 45%, 49%, and 25% respectively at 50 months follow-up. These differences reached clinical relevance by 20 months after treatment. Baseline ED rate was 38% and increased to 71% after treatment (p = 0.024). Use of ED medications was 3% at baseline and progressed to 25%. For patients aged <70 years at follow-up, 60% maintained satisfactory erectile function after treatment compared with only 12% aged ≥70 years (p = 0.008). Penile bulb dose was not associated with ED.Conclusions: The rates of ED after treatment appear comparable to those reported for other modalities of radiotherapy. Given the modest size of this study and the uncertainties in the physiology of radiotherapy-related ED, these results merit further investigations.

Behavior of Lipiodol Markers During Image Guided Radiotherapy of Bladder Cancer - Corrected Proof

2010-02-04

Purpose: To investigate the stability of a novel type of markers used in partial bladder tumor irradiation and tumor deformation as indicated by the markers.Materials and Methods: In 15 patients with solitary bladder cancer, lipiodol was injected in the bladder wall during flexible cystoscopy to identify the tumor. A planning CT scan was made, followed by daily cone-beam CT (CBCT) scans during treatment. To study the accuracy of using these markers for image guidance, uncertainties U1 and U2 were calculated, which were defined as the difference between submask registration (covering single marker) and the average of all submask registrations and the difference between the submask registration and the general mask registration (including all markers), respectively. Finally, to study tumor deformation, the relative movement of each marker pair was correlated with the relative bladder volume (RBV).Results: The analyzed patients had 2.3 marker injections on average. The lipiodol spot size was 0.72 ± 1.1 cm3. The intensity of spots in both CT and CBCT was significantly higher than the surrounding bladder tissue. The uncertainties U1 and U2 were comparable, and the uncertainties in left-right direction (0.14–0.19 cm) were smaller than those in cranial-caudal and anterior-posterior directions (0.19–0.32 cm). The relative marker movement of within-zone marker pairs was much smaller (and has less dependence on the RBV) than across-zones marker pairs.Conclusions: Lipiodol markers are a feasible method to track bladder tumor by using online CBCT. Tumor deformation is observed, especially for tumors that cross the defined bladder zones.