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

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.

Evaluation of Late Adverse Events in Long-term Wilms' Tumor Survivors - Corrected Proof

2010-02-04

Purpose: To evaluate the prevalence and severity of adverse events (AEs) and treatment-related risk factors in long-term Wilms' tumor (WT) survivors, with special attention to radiotherapy.Methods and Materials: The single-center study cohort consisted of 185 WT survivors treated between 1966 and 1996, who survived at least 5 years after diagnosis. All survivors were invited to a late-effects clinic for medical assessment of AEs. AEs were graded for severity in a standardized manner. Detailed radiotherapy data enabled us to calculate the equivalent dose in 2 Gy fractions (EQD2) to compare radiation doses in a uniform way. Risk factors were evaluated with multivariate logistic regression analysis.Results: Medical follow-up was complete for 98% of survivors (median follow-up, 18.9 years; median attained age, 22.9 years); 123 survivors had 462 AEs, of which 392 had Grade 1 or 2 events. Radiotherapy to flank/abdomen increased the risk of any AE (OR, 1.08 Gy−1 [CI, 1.04–1.13]). Furthermore, radiotherapy to flank/abdomen was associated with orthopedic events (OR, 1.09 Gy−1 [CI, 1.05–1.13]) and second tumors (OR, 1.11 Gy−1 [CI, 1.03–1.19]). Chest irradiation increased the risk of pulmonary events (OR, 1.14 Gy−1 [CI, 1.06–1.21]). Both flank/abdominal and chest irradiation were associated with cardiovascular events (OR, 1.05 Gy−1 [CI, 1.00–1.10], OR, 1.06 Gy−1 [CI, 1.01–1.12]) and tissue hypoplasia (OR, 1.17 Gy−1 [CI, 1.10–1.24], OR 1.10 Gy−1 [CI, 1.03–1.18]).Conclusion: The majority of AEs, overall as well as in irradiated survivors, were mild to moderate. Nevertheless, the large amount of AEs emphasizes the importance of follow-up programs for WT survivors.

Total Body Irradiation Compared with BEAM: Long-Term Outcomes of Peripheral Blood Autologous Stem Cell Transplantation for Non-Hodgkin's Lymphoma - Corrected Proof

2010-02-04

Purpose: The optimal preparative regimen for non-Hodgkin's lymphoma patients undergoing autologous peripheral blood stem cell transplantation (PBSCT) is unknown. We compared a total body irradiation (TBI)-based regimen with a chemotherapy-alone regimen.Methods and Materials: A retrospective cohort study was performed at a Canadian cancer center. The TBI regimen consisted of cyclophosphamide, etoposide, and TBI 12 Gy in six fractions (CY/E/TBI). The chemotherapy-alone regimen consisted of carmustine, etoposide, cytarabine, and melphalan (BEAM). We compared the acute and long-term toxicities, disease relapse-free survival, and overall survival (OS).Results: Of 73 patients, 26 received CY/E/TBI and 47 received BEAM. The median follow-up for the CY/E/TBI group was 12.0 years and for the BEAM group was 7.3 years. After PBSCT, no differences in acute toxicity were seen between the two groups. The 5-year disease relapse-free survival rate was 50.0% and 50.7% in the CY/E/TBI and BEAM groups, respectively (p = .808). The 5-year OS rate was 53.9% and 63.8% for the CY/E/TBI and BEAM groups, respectivey (p = .492). The univariate analysis results indicated that patients with Stage IV, with chemotherapy-resistant disease, and who had received PBSCT before 2000 had inferior OS. A three-way categorical analysis revealed that transplantation before 2000, rather than the conditioning regimen, was a more important predictive factor of long-term outcome (p = .034).Conclusion: A 12-Gy TBI-based conditioning regimen for PBSCT for non-Hodgkin's lymphoma resulted in disease relapse-free survival and OS similar to that after BEAM. PBSCT before 2000, and not the conditioning regimen, was an important predictor of long-term outcomes. TBI was not associated with more acute toxicity or pneumonitis. We found no indication that the TBI regimen was inferior or superior to BEAM.

Phase I Trial of Bortezomib and Concurrent External Beam Radiation in Patients with Advanced Solid Malignancies - Corrected Proof

2010-02-03

Purpose: To determine the maximal tolerated dose of bortezomib with concurrent external beam radiation therapy in patients with incurable solid malignant tumors requiring palliative therapy.Methods and Materials: An open label, dose escalation, phase I clinical trial evaluated the safety of three dose levels of bortezomib administered intravenously (1.0mg/m2, 1.3mg/m2, and 1.6mg/m2/ dose) once weekly with concurrent radiation in patients with histologically confirmed solid tumors and a radiographically appreciable lesion suitable for palliative radiation therapy. All patients received 40 Gy in 16 fractions to the target lesion. Dose-limiting toxicity was the primary endpoint, defined as any grade 4 hematologic toxicity, any grade ≥3 nonhematologic toxicity, or any toxicity requiring treatment to be delayed for ≥2 weeks.Results: A total of 12 patients were enrolled. Primary sites included prostate (3 patients), head and neck (3 patients), uterus (1 patient), abdomen (1 patient), breast (1 patient), kidney (1 patient), lung (1 patient), and colon (1 patient). The maximum tolerated dose was not realized with a maximum dose of 1.6mg/m2. One case of dose-limiting toxicity was appreciated (grade 3 urosepsis) and felt to be unrelated to bortezomib. The most common grade 3 toxicity was lymphopenia (10 patients). Common grade 1 to 2 events included nausea (7 patients), infection without neutropenia (6 patients), diarrhea (5 patients), and fatigue (5 patients).Conclusions: The combination of palliative external beam radiation with concurrent weekly bortezomib therapy at a dose of 1.6mg/m2 is well tolerated in patients with metastatic solid tumors. The maximum tolerated dose of once weekly bortezomib delivered concurrently with radiation therapy is greater than 1.6mg/m2.

Preoperative Radiotherapy of advanced rectal cancer with Capecitabine and Oxaliplatin with or without Cetuximab: A Pooled Analysis of Three Prospective Phase I-II Trials - Corrected Proof

2010-02-03

Purpose: A pooled analysis of three prospective trials of preoperative radiochemotherapy (RCT) for rectal cancer by using oxaliplatin and capecitabine with or without cetuximab was performed to evaluate the impact of additional cetuximab on pathologic complete response (pCR) rates and tumor regression (TRG) grades.Methods and Materials: Of 202 patients, 172 patients met the inclusion criteria (primary tumor stage II/III, M0). All patients received concurrent RCT, and 46 patients received additional cetuximab therapy. A correlation of pretreatment clinicopathologic factors and cetuximab treatment with early pCR rates (TRG > 50%) was performed with univariate and multivariate analyses. Toxicity data were recorded for all patients.Results: Of 172 patients, 24 (14%) patients achieved a pCR, and 84 of 172 (71%) patients showed a TRG of >50% in the surgical specimen assessment after preoperative treatment. Age, gender, and T/N stages, as well as localization of the tumor, were not associated with pCR or good TRG. The pCR rate was 16% after preoperative RCT alone and 9% with concurrent cetuximab therapy (p = 0.32). A significantly reduced TRG of >50% was found after RCT with cetuximab compared to RCT alone (p = 0.0035). This was validated by a multivariate analysis with all available clinical factors (p = 0.0037). Acute toxicity and surgical complications were not increased with additional cetuximab.Conclusions: Triple therapy with RCT and cetuximab seems to be feasible, with no unexpected toxicity. Early response assessment (TRG), however, suggests subadditive interaction. A longer follow-up (and finally randomized trials) is needed to draw any firm conclusions with respect to local and distant failure rates.

Prognostic Factors after Extraneural Metastasis of Medulloblastoma - Corrected Proof

Ali Mazloom, Azy H. Zangeneh, Arnold C. Paulino — 2010-02-03

Purpose: To review the existing literature regarding the characteristics, prognostic factors, treatment, and survival of patients with medulloblastoma, who develop extraneural metastasis (ENM).Methods and Materials: A PubMed search of English language articles from 1961 to 2007 was performed, yielding 47 articles reporting on 119 patients. Factors analyzed included age, time interval to development of ENM, ENM location, central nervous system (CNS) involvement, treatment, and outcome.Results: Sites of ENM included bone in 84% of patients, bone marrow in 27% of patients, lymph nodes in 15% of patients, lung in 6% of patients, and liver in 6% of patients. Median survival was 8 months after diagnosis of ENM. The 1-, 2-, and 5-year overall survival (OS) rates after diagnosis of ENM were 41.9%, 31.0%, and 26.0%, respectively. The 1-, 2-, and 5-year progression-free survival (PFS) rates after diagnosis of ENM were 34.5%, 23.2%, and 13.4%, respectively. For patients without CNS involvement at the time of ENM diagnosis, the 1-, 2-, and 5-year OS rates for those treated with and without radiotherapy (RT) were 82.4%, 64.8%, and 64.8% vs. 51.0%, 36.6%, and 30.5%, respectively (p = 0.03, log-rank test). RT did not significantly improve OS or PFS rates for those with CNS involvement. Concurrent CNS involvement, ENM in the lung or liver, a time interval of <18 months to development of ENM, and a patient age of <16 years at ENM diagnosis were found to be negative prognostic factors for both OS and PFS.Conclusions: Several prognostic factors were identified for patients with ENM from medulloblastoma. Patients without concurrent CNS involvement, who received RT after ENM diagnosis had an OS and PFS benefit compared to those who did not receive RT.

Stereotactic Radiosurgery for Treatment of Spinal Metastases Recurring in Close Proximity to Previously Irradiated Spinal Cord - Corrected Proof

2010-02-03

Purpose: As the spinal cord tolerance often precludes reirradiation with conventional techniques, local recurrence within a previously irradiated field presents a treatment challenge.Methods and Materials: We retrospectively reviewed 51 lesions in 42 patients treated from 2002 to 2008 whose spinal metastases recurred in a previous radiation field (median previous spinal cord dose of 40 Gy) and were subsequently treated with stereotactic radiosurgery (SRS).Results: SRS was delivered to a median marginal dose of 20 Gy (range, 10–30 Gy) in 1–5 fractions (median, 2), targeting a median tumor volume of 10.3 cm3 (range, 0.2–128.6 cm3). Converting the SRS regimens with the linear quadratic model (α/β = 3), the median spinal cord maximum single-session equivalent dose (SSED) was 12.1 Gy3 (range, 4.7–19.3 Gy3). With a median follow-up of 7 months (range, 2–47 months), the Kaplan-Meier local control and overall survival rates at 6/12 months were 87%/73% and 81%/68%, respectively. A time to retreatment of ≤12 months and the combination of time to retreatment of ≤12 months with an SSED of <15 Gy10 were significant predictors of local failure on univariate and multivariate analyses. In patients with a retreatment interval of <12 months, 6/12 month local control rates were 88%/58%, with a SSED of >15 Gy10, compared to 45%/0% with <15 Gy10, respectively. One patient (2%) experienced Grade 4 neurotoxicity.Conclusion: SRS is safe and effective in the treatment of spinal metastases recurring in previously irradiated fields. Tumor recurrence within 12 months may correlate with biologic aggressiveness and require higher SRS doses (SSED >15 Gy10). Further research is needed to define the partial volume retreatment tolerance of the spinal cord and the optimal target dose.

Angiogenic Blockade and Radiotherapy in Hepatocellular Carcinoma - Corrected Proof

2010-02-03

Purpose: We report our preliminary experience of combining sunitinib and helical tomotherapy in patients with advanced HCC.Methods and Materials: Records of patients with advanced hepatocellular carcinoma (HCC) treated with helical tomotherapy and sunitinib after radiation therapy (RT) from March 2007 to August 2008 were retrospectively reviewed. We report acute toxicities, radiologic response, serial α-fetoprotein (AFP) kinetics, and survival.Results: Of 23 evaluable patients, 60% had ≥2 hepatic lesions, extrahepatic disease was present in 5 (21.7%), and all received 2 tablets (25 mg) of sunitinib at least 1 week before, during, and 2 weeks after RT. Thirteen patients continued maintenance sunitinib after RT until disease progression. Hypofractionated RT with a median target dose of 52.5 Gy/15 fractions was delivered. An objective response was achieved in 74% of patients. The 1-year survival rate was 70%, with median survival of 16 months. Multivariate analysis showed that maintenance sunitinib was the most significant factor for survival. The time to progression was 10 months in the maintenance group compared with 4 months in the control group. Eighteen out of 21 patients with elevated AFP (85.7%) had ≧50% decline of AFP within 2 months after RT. There were three episodes of upper gastrointestinal bleeding and one episode of pancreatitis; 10 patients had ≥Grade 2 elevation of liver enzymes, and 15 had ≥Grade 2 thrombocytopenia.Conclusions: These preliminary results suggest that sunitinib and helical tomotherapy yield high Response Evaluation Criteria in Solid Tumors (RECIST) and AFP response rates in advanced HCC with an acceptable safety profile. Maintenance sunitinib after RT potentially prolongs survival. A randomized trial is warranted.

Evaluating the Phoenix definition of biochemical failure after 125I prostate brachytherapy: Can PSA kinetics distinguish PSA failures from PSA bounces? - Corrected Proof

2010-02-03

Purpose: To evaluate the prostate-specific antigen (PSA) kinetics of PSA failure (PSAf) and PSA bounce (PSAb) after permanent 125I prostate brachytherapy (PB).Methods and Materials: The study included 1,006 consecutive low and “low tier” intermediate-risk patients treated with 125I PB, with a potential minimum follow-up of 4 years. Patients who met the Phoenix definition of biochemical failure (nadir + 2 ng/mL−1) were identified. If the PSA subsequently fell to ≤0.5 ng/mL−1without intervention, this was considered a PSAb. All others were scored as true PSAf. Patient, tumor and dosimetric characteristics were compared between groups using the chi-square test and analysis of variance to evaluate factors associated with PSAf or PSAb.Results: Median follow-up was 54 months. Of the 1,006 men, 57 patients triggered the Phoenix definition of PSA failure, 32 (56%) were true PSAf, and 25 PSAb (44%). The median time to trigger nadir + 2 was 20.6 months (range, 6–36) vs. 49 mo (range, 12–83) for PSAb vs. PSAf groups (p < 0.001). The PSAb patients were significantly younger (p < 0.0001), had shorter time to reach the nadir (median 6 vs. 11.5 months, p = 0.001) and had a shorter PSA doubling time (p = 0.05). Men younger than age 70 who trigger nadir +2 PSA failure within 38 months of implant have an 80% likelihood of having PSAb and 20% chance of PSAf.Conclusions: With adequate follow-up, 44% of PSA failures by the Phoenix definition in our cohort were found to be benign PSA bounces. Our study reinforces the need for adequate follow-up when reporting PB PSA outcomes, to ensure accurate estimates of treatment efficacy and to avoid unnecessary secondary interventions.

Increased Detection of Lymphatic Vessel Invasion by D2-40 (Podoplanin) in Early Breast Cancer: Possible Influence on Patient Selection for Accelerated Partial Breast Irradiation - Corrected Proof

2010-02-03

Purpose: Several international trials are currently investigating accelerated partial breast irradiation (APBI) for patients with early-stage breast cancer. According to existing guidelines, patients with lymphatic vessel invasion (LVI) do not qualify for APBI. D2-40 (podoplanin) significantly increases the frequency of LVI detection compared with conventional hematoxylin and eosin (HE) staining in early-stage breast cancer. Our purpose was to retrospectively assess the hypothetical change in management from APBI to whole breast radiotherapy with the application of D2-40.Patients and Methods: Immunostaining with D2-40 was performed on 254 invasive breast tumors of 247 patients. The following criteria were used to determine the eligibility for APBI: invasive ductal adenocarcinoma of ≤3 cm, negative axillary node status (N0), and unifocal disease. Of the 247 patients, 74 with available information concerning LVI, as detected by D2-40 immunostaining and routine HE staining, formed our study population.Results: Using D2-40, our results demonstrated a significantly greater detection rate (p = .031) of LVI compared with routine HE staining. LVI was correctly identified by D2-40 (D2-40–positive LVI) in 10 (13.5%) of 74 tumors. On routine HE staining, 4 tumors (5.4%) were classified as HE-positive LVI. Doublestaining of these specimens with D2-40 unmasked false-positive LVI status in 2 (50%) of the 4 tumors. According to the current recommendations for APBI, immunostaining with D2-40 would have changed the clinical management from APBI to whole breast radiotherapy in 8 (10.8%) of 74 patients and from whole breast radiotherapy to APBI in 2 patients (2.7%).Conclusion: These data support the implementation of D2-40 immunostaining in the routine workup to determine a patient's eligibility for APBI.

Correlation Between Acute and Late Toxicity in 973 Prostate Cancer Patients Treated with Three-Dimensional Conformal External Beam Radiotherapy - Corrected Proof

2010-02-03

Purpose: To analyze the correlation between acute and late injury in 973 prostate cancer patients treated with radiotherapy and to evaluate the effect of patient-, tumor-, and treatment-related variables on toxicity.Methods and Materials: Of the 973 patients, 542 and 431 received definitive or postprostatectomy radiotherapy, respectively. Three-dimensional conformal radiotherapy included a six-field technique and two-dynamic arc therapy. Toxicity was classified according to the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. The correlation between acute and late toxicity (incidence and severity) was assessed.Results: Multivariate analysis showed that age ≤65 years (p = .06) and use of the three-dimensional, six-field technique (p 70 Gy (p = .014), and radiotherapy duration (p = .05) correlated with greater acute urinary toxicity. Acute rectal toxicity (p <.0001) was the only factor that correlated with late rectal injury on multivariate analysis. Late urinary toxicity correlated with acute urinary events (p <.0001) and was inversely related to the use of salvage radiotherapy (p = .018). A highly significant correlation was found between the incidence of acute and late events for both rectal (p <.001) and urinary (p <.001) reactions. The severity of acute toxicity (Grade 2 or greater) was predictive for the severity of late toxicity for both rectal and urinary events (p <.001).Conclusion: The results of our study have shown that the risk of acute reactions depends on both patient-related (age) and treatment-related (dose, technique) factors. Acute toxicity was an independent significant predictor of late toxicity. These findings might help to predict and prevent late radiotherapy-induced complications.

Lack of Correlation Between External Fiducial Positions and Internal Tumor Positions During Breath-Hold CT - Corrected Proof

Sandeep Hunjan, George Starkschall, Karl Prado, Lei Dong, Peter Balter — 2010-02-03

Purpose: For thoracic tumors, if four-dimensional computed tomography (4DCT) is unavailable, the internal margin can be estimated by use of breath-hold (BH) CT scans acquired at end inspiration (EI) and end expiration (EE). By use of external surrogates for tumor position, BH accuracy is estimated by minimizing the difference between respiratory extrema BH and mean equivalent-phase free breathing (FB) positions. We tested the assumption that an external surrogate for BH accuracy correlates with internal tumor positional accuracy during BH CT.Methods and Materials: In 16 lung cancer patients, 4DCT images, as well as BH CT images at EI and EE, were acquired. Absolute differences between BH and mean equivalent-phase (FB) positions were calculated for both external fiducials and gross tumor volume (GTV) centroids as metrics of external and internal BH accuracy, respectively, and the results were correlated.Results: At EI, the absolute difference between mean FB and BH fiducial displacement correlated poorly with the absolute difference between FB and BH GTV centroid positions on CT images (R2 = 0.11). Similarly, at EE, the absolute difference between mean FB and BH fiducial displacements correlated poorly with the absolute difference between FB and BH GTV centroid positions on CT images (R2 = 0.18).Conclusions: External surrogates for tumor position are not an accurate metric of BH accuracy for lung cancer patients. This implies that care should be taken when using such an approach because an incorrect internal margin could be generated.

Fractionated Conformal Radiotherapy in the Management of Cavernous Sinus Meningiomas: Long-Term Functional Outcome and Tumor Control at a Single Institution - Corrected Proof

2010-02-03

Purpose: To evaluate long-term outcome of cavernous sinus meningioma (CSM) treated with fractionated conformal radiotherapy (FCR).Patients and Methods: Fifty-three patients with CSMs (16 men [30.2%], 37 women [69.8%], aged 53 ± 13.0 years [mean ± SD]) were treated by FCR. In 28 patients (52.8%) FCR was performed as first-line treatment and in 25 patients (47.2%) as adjuvant treatment. All patients received FCR with a dose of 52.9 ± 1.8 Gy in 29.4 ± 1.0 fractions over 6 weeks. Dose per fraction was 1.9 ± 0.1 Gy. Radiotherapy was delivered stereotactically in 47 cases (88.7%) and conformally in 6 (11.3%)Results: The median follow-up was 6.9 years (range, 3–19 years). According to Sekhar's classification, 19 patients (35.8%) were Grade 1–2, 30 patients (56.6%) were Grade 3–4, and 4 patients (7.6%) were Grade 5. Pretreatment tumor volume was determined in 46 patients, and tumor volume was 12.6 ± 8.2 cm3. In these patients, the distance between tumor and optic apparatus was 1.62 ± 1.2 mm. Actuarial 5- and 10-year progression-free survival rates were 98.1% and 95.8%, respectively. Clinical improvement was observed in 31 patients (58.5%), and 20 patients (37.7%) remained unchanged. Radiologic response was observed in 18 patients (30.2%), and 35 patients (66.0%) showed stable lesions. Two patients (3.8%) showed tumor progression during follow-up. Transient morbidity was observed in 3 patients (5.7%) and permanent morbidity in 1 (1.9%).Conclusion: Fractionated conformal radiotherapy affords satisfactory long-term tumor control and low treatment morbidity.

Gated Treatment Delivery Verification with On-Line Megavoltage Fluoroscopy - Corrected Proof

2010-02-03

Purpose: To develop and clinically demonstrate the use of on-line real-time megavoltage (MV) fluoroscopy for gated treatment delivery verification.Methods and Materials: Megavoltage fluoroscopy (MVF) image sequences were acquired using a flat panel equipped for MV cone-beam CT in synchrony with the respiratory signal obtained from the Anzai gating device. The MVF images can be obtained immediately before or during gated treatment delivery. A prototype software tool (named RTReg4D) was developed to register MVF images with phase-sequenced digitally reconstructed radiograph images generated from the treatment planning system based on four-dimensional CT. The image registration can be used to reposition the patient before or during treatment delivery. To demonstrate the reliability and clinical usefulness, the system was first tested using a thoracic phantom and then prospectively in actual patient treatments under an institutional review board–approved protocol.Results: The quality of the MVF images for lung tumors is adequate for image registration with phase-sequenced digitally reconstructed radiographs. The MVF was found to be useful for monitoring inter- and intrafractional variations of tumor positions. With the planning target volume contour displayed on the MVF images, the system can verify whether the moving target stays within the planning target volume margin during gated delivery.Conclusions: The use of MVF images was found to be clinically effective in detecting discrepancies in tumor location before and during respiration-gated treatment delivery. The tools and process developed can be useful for gated treatment delivery verification.

Renal Atrophy Secondary to Chemoradiotherapy of Abdominal Malignancies - Corrected Proof

2010-02-03

Purpose: To identify factors predictive of renal atrophy after chemoradiotherapy of gastrointestinal malignancies.Methods and Materials: Patients who received chemotherapy and abdominal radiotherapy (RT) between 2002 and 2008 were identified for this study evaluating change in kidney size and function after RT. Imaging and biochemical data were obtained before and after RT in 6-month intervals. Kidney size was defined by craniocaudal measurement on CT images. The primarily irradiated kidney (PK) was defined as the kidney that received the greater mean kidney dose. Receiver operating characteristic (ROC) curves were generated to predict risk for renal atrophy.Results: Of 130 patients, median age was 64 years, and 51.5% were male. Most primary disease sites were pancreas and periampullary tumors (77.7%). Median follow-up was 9.4 months. Creatinine clearance declined 20.89%, and size of the PK decreased 4.67% 1 year after completion of chemoradiation. Compensatory hypertrophy of the non-PK was not seen. Percentage volumes of the PK receiving ≥10 Gy (V10), 15 Gy (V15), and 20 Gy (V20) were significantly associated with renal atrophy 1 year after RT (p = 0.0030, 0.0029, and 0.0028, respectively). Areas under the ROC curves for V10, V15, and V20 to predict >5% decrease in PK size were 0.760, 0.760, and 0.762, respectively.Conclusions: Significant detriments in PK size and renal function were seen after abdominal RT. The V10, V15, and V20 were predictive of risk for PK atrophy 1 year after RT. Analyses suggest the association of lower-dose renal irradiation with subsequent development of renal atrophy.

Dose Gradient Near Target–Normal Structure Interface for Nonisocentric CyberKnife and Isocentric Intensity-Modulated Body Radiotherapy for Prostate Cancer - Corrected Proof

2010-02-03

Purpose: The treatment planning quality between nonisocentric CyberKnife (CK) and isocentric intensity modulation treatment was studied for hypofractionated prostate body radiotherapy. In particular, the dose gradient across the target and the critical structures such as the rectum and bladder was characterized.Methods and Materials: In the present study, patients treated with CK underwent repeat planning for nine fixed-field intensity-modulated radiotherapy (IMRT) using identical contour sets and dose–volume constraints. To calculate the dose falloff, the clinical target volume contours were expanded 30 mm anteriorly and posteriorly and 50 mm uniformly in other directions for all patients in the CK and IMRT plans.Results: We found that all the plans satisfied the dose–volume constraints, with the CK plans showing significantly better conformity than the IMRT plans at a relative greater dose inhomogeneity. The rectal and bladder volumes receiving a low dose were also lower for CK than for IMRT. The average conformity index, the ratio of the prescription isodose volume and clinical target volume, was 1.18 ± 0.08 for the CK plans vs. 1.44 ± 0.11 for the IMRT plans. The average homogeneity index, the ratio of the maximal dose and the prescribed dose to the clinical target volume, was 1.45 ± 0.12 for the CK plans vs. 1.28 ± 0.06 for the IMRT plans. The average percentage of dose falloff was 2.9% ± 0.8%/mm for CK and 3.1% ± 1.0%/mm for IMRT in the anterior direction, 3.8% ± 1.6%/mm for CK and 3.2% ± 1.9%/mm for IMRT in the posterior direction, and 3.6% ± 0.4% for CK and 3.6% ± 0.4% for IMRT in all directions.Conclusion: Nonisocentric CK was as capable of producing equivalent fast dose falloff as high-number fixed-field IMRT delivery.

Effect of Radiotherapy Interruptions on Survival in Medicare Enrollees with Local and Regional Head-and-Neck Cancer - Corrected Proof

Megan Dann Fesinmeyer, Vivek Mehta, David Blough, Lauri Tock, Scott D. Ramsey — 2010-02-03

Purpose: To investigate whether interruptions in radiotherapy are associated with decreased survival in a population-based sample of head-and-neck cancer patients.Methods and Materials: Using the Surveillance, Epidemiology, and End Results–Medicare linked database we identified Medicare beneficiaries aged 66 years and older diagnosed with local–regional head-and-neck cancer during the period 1997–2003. We examined claims records of 3864 patients completing radiotherapy for the presence of one or more 5–30-day interruption(s) in therapy. We then performed Cox regression analyses to estimate the association between therapy interruptions and survival.Results: Patients with laryngeal tumors who experienced an interruption in radiotherapy had a 68% (95% confidence interval, 41–200%) increased risk of death, compared with patients with no interruptions. Patients with nasal cavity, nasopharynx, oral, salivary gland, and sinus tumors had similar associations between interruptions and increased risk of death, but these did not reach statistical significance because of small sample sizes.Conclusions: Treatment interruptions seem to influence survival time among patients with laryngeal tumors completing a full course of radiotherapy. At all head-and-neck sites, the association between interruptions and survival is sensitive to confounding by stage and other treatments. Further research is needed to develop methods to identify patients most susceptible to interruption-induced mortality.

Stereotactic Radiosurgery for Single Brainstem Metastases: The Cleveland Clinic Experience - Corrected Proof

2010-02-03

Purpose: To assess the imaging and clinical outcomes of patients with single brainstem metastases treated with stereotactic radiosurgery (SRS).Materials and Methods: We retrospectively reviewed the data from patients with single brainstem metastases treated with SRS. Locoregional control and survival were calculated using the Kaplan-Meier method. Prognostic factors were assessed using a Cox proportional hazards model.Results: Between 1997 and 2007, 43 patients with single brainstem metastases were treated with SRS. The median age at treatment was 59 years, the median Karnofsky performance status was 80, and the median follow-up was 5.3 months. The median dose was 15 Gy (range, 9.6–24), and the median conformality and heterogeneity index was 1.7 and 1.9, respectively. The median survival was 5.8 months from the procedure date. Of the 33 patient with post-treatment imaging available, a complete radiographic response was achieved in 2 (4.7%), a partial response in 8 (18.6%), and stable disease in 23 (53.5%). The 1-year actuarial rate of local control, distant brain control, and overall survival was 85%, 38.3%, and 31.5%, respectively. Of the 43 patients, 8 (19%) died within 2 months of undergoing SRS, and 15 (36%) died within 3 months. On multivariate analysis, greater performance status (hazard ratio [HR], 0.95, p = .004), score index for radiosurgery (HR, 0.7; p = .004), graded prognostic assessment score (HR, 0.48; p = .003), and smaller tumor volume (HR, 1.23, p = .002) were associated with improved survival. No Grade 3 or 4 toxicities were observed.Conclusion: The results of our study have shown that SRS is a safe and effective local therapy for patients with brainstem metastases.

Predictive and Prognostic Significance of Glutathione Levels and DNA Damage in Cervix Cancer Patients Undergoing Radiotherapy - Corrected Proof

2010-02-03

Purpose: To assess the predictive significance of serum glutathione (GSH) and tumor tissue DNA damage in the treatment of cervical cancer patients undergoing chemoradiotherapy.Methods and Materials: This study included subjects undergoing hysterectomy (for normal cervix tissue) and cervical cancer patients who underwent conventional concurrent chemoradiotherapy (cisplatin once per week for 5 weeks with concurrent external radiotherapy of 2 Gy per fraction for 5 weeks, followed by two applications of intracavitary brachytherapy once per week after 2 weeks' rest). Blood was collected after two fractions, whereas both blood and tissues were collected after five fractions of radiotherapy in separate groups of subjects. Serum for total GSH content and tissues were processed for single-cell gel electrophoresis (SCGE) assay for DNA damage analysis. Clinical tumor radioresponse was assessed 2 months after the completion of treatment as complete responders (CR) (100% shrinkage), partial responders (PR) (>50%), and nonresponders (NR) (<50%).Results: Serum GSH content depleted significantly after a total dose of 4 Gy and 10 Gy of radiotherapy with a single dose of cisplatin, which was significantly lesser in NR than of CR patients. Similarly, Olive Tail Moment, the index of DNA damage, indicated significantly higher values in the fifth fraction of radiotherapy (5-RT) than in pretreatment. The DNA damage after 5-RT in the NR subgroup was significantly lower than that of CR.Conclusions: Serum GSH analysis and tumor tissue SCGE assay found to be useful parameters for predicting chemoradioresponse prior to and also at an early stage of treatment of cervical cancers.

18F-FDG PET Definition of Gross Tumor Volume for Radiotherapy of Lung Cancer: Is the Tumor Uptake Value-based Approach Appropriate for Lymph Node Delineation? - Corrected Proof

2010-02-03

Purpose: Positron emission tomography (PET) with the glucose analogue [18F] fluoro-2-deoxy-D-glucose (18F-FDG-PET) has been used in radiation treatment planning for non-small-cell carcinoma. To date, lymph nodes have been contoured according to the uptake of the tumor. This prospective study was performed to evaluate if nodal volume delineates according to FDG uptake within the primary tumor (PET-GTVnt) is suitable for nodal target volume delineation or if individualized nodal FDG uptake measure (PET-GTVnn) is necessary to better nodal target definition.Methods and Materials: Forty cases, who underwent a diagnostic 18F-FDG PET/computed tomography (CT) scan, were included. Two PET-based GTVs for each lymph node were contoured and compared. First, we used an isocontour of 40% of the maximum tumor uptake (PET-GTVnt). Second, an isocontour of 40% of the maximum uptake of each node (PET-GTVnn) was employed. To avoid interobserver variability, this was carried out by the same radiation oncologist. Afterwards, the difference between both lymph node volumes was plotted against the ratio of the maximum uptakes (In/It) in a linear regression analysis.Results: Compared with CT-based lymph node volume (CT-GTVn), the intraclass correlation coefficient of PET-GTVnn was higher than the coefficient of PET-GTVnt (p < 0.001). All cases could be divided into four groups: undetected (17.5%), detected but overestimated (10%), detected but underestimated (35%), and correctly detected (37.5%).Conclusions: If a method of automatic delineation shall be applied, this method must be applied to every lesion separately. However, to facilitate the delineation in daily practice, when In/It is ≤25%, lymph nodes could be delineated in accordance with tumor uptake, keeping an absolute difference in radii <5 mm.

Multicenter, Phase 3 Trial Comparing Selenium Supplementation With Observation in Gynecologic Radiation Oncology - Corrected Proof

2010-02-03

Purpose: We assessed whether adjuvant supplementation with selenium improves the selenium status and reduces side effects of patients treated by radiotherapy (RT) for cervical and uterine cancer.Methods and Materials: Whole-blood selenium concentrations were measured in patients with cervical cancer (n = 11) and uterine cancer (n = 70) after surgical treatment, during RT, at the end of RT, and 6 weeks after RT. Patients with initial selenium concentrations of less than 84μg/L were randomized before RT either to receive 500 μg of selenium (in the form of sodium selenite [selenase®, biosyn Arzneimittel GmbH, Fellbach, Germany]) by mouth on the days of RT and 300 μg of selenium on the days without RT or to receive no supplement during RT. The primary endpoint of this multicenter Phase 3 study was to assess the efficiency of selenium supplementation during RT; the secondary endpoint was to decrease radiation-induced diarrhea and other RT-dependent side effects.Results: A total of 81 patients were randomized. We enrolled 39 in the selenium group (SG) and 42 in the control group (CG). Selenium levels did not differ between the SG and CG upon study initiation but were significantly higher in the SG at the end of RT. The actuarial incidence of diarrhea of Grade 2 or higher according to Common Toxicity Criteria (version 2) in the SG was 20.5% compared with 44.5% in the CG (p = 0.04). Other blood parameters, Eastern Cooperative Oncology Group performance status, and self-reported quality of life were not different between the groups.Conclusions: Selenium supplementation during RT is effective in improving blood selenium status in selenium-deficient cervical and uterine cancer patients and reduces the number of episodes and severity of RT-induced diarrhea.

Influence of Continuous Table Motion on Patient Breathing Patterns - Corrected Proof

2010-02-03

Purpose: To investigate the influence of continuous table motion on patient breathing patterns for compensation of moving targets by a robotic treatment couch.Methods and Materials: Fifteen volunteers were placed on a robotic treatment couch, and the couch was moved on different breathing-correlated and -uncorrelated trajectories. External abdominal breathing motion of the patients was measured using an infrared camera system. The influence of table motion on breathing range and pattern was analyzed.Results: Continuous table motion was tolerated well by all test persons. Volunteers reacted differently to table motion. Four test persons showed no change of breathing range and pattern. Increased irregular breathing was observed in 4 patients; however, irregularity was not correlated with table motion. Only 4 test persons showed an increase in mean breathing amplitude of more than 2mm during motion of the couch. The mean cycle period decreased by more than 1 s for 2 test persons only. No abrupt changes in amplitude or cycle period could be observed.Conclusions: The observed small changes in breathing patterns support the application of motion compensation by a robotic treatment couch.

Dynamic Multileaf Collimator Tracking of Respiratory Target Motion Based On a Single Kilovoltage Imager During Arc Radiotherapy - Corrected Proof

Per Rugaard Poulsen, Byungchul Cho, Dan Ruan, Amit Sawant, Paul J. Keall — 2010-02-03

Purpose: To demonstrate and characterize dynamic multileaf collimator (DMLC) tracking of respiratory moving targets that are spatially localized with a single kV X-ray imager during arc radiotherapy.Methods and Materials: During delivery of an arc field (358° gantry rotation, 72-sec duration, circular field shape), the three-dimensional (3D) position of a fiducial marker in a phantom was estimated in real time from fluoroscopic kV X-ray images acquired orthogonally to the treatment beam axis. A prediction algorithm was applied to account for system latency (570 ms) before the estimated marker position was used for DMLC aperture adaptation. Experiments were performed with 12 patient-measured tumor trajectories that were selected from 160 trajectories (46 patients) and reproduced by a programmable phantom. Offline, the 3D deviation of the estimated phantom position from the actual position was quantified. The two-dimensional (2D) beam-target deviation was quantified as the positional difference between the MLC aperture center and the marker in portal images acquired continuously during experiments. Simulations of imaging and treatment delivery extended the study to all 160 tumor trajectories and to arc treatments of 3-min and 5-min duration.Results: In the experiments, the mean root-mean-square deviation was 1.8 mm for the 3D target position and 1.5 mm for the 2D aperture position. Simulations agreed with this to within 0.1 mm and resulted in mean 2D root-mean-square beam-target deviations of 1.1 mm for all 160 trajectories for all treatment durations. The deviations were mainly caused by system latency (570 ms).Conclusions: Single-imager DMLC tracking of respiratory target motion during arc radiotherapy was implemented, providing less than 2-mm geometric uncertainty for most trajectories.

Predicting Post–External Beam Radiation Therapy PSA Relapse of Prostate Cancer Using Pretreatment MRI - Corrected Proof

2010-02-03

Purpose: To investigate whether pretreatment endorectal magnetic resonance imaging (MRI) findings can predict biochemical relapse in patients with clinically localized prostate cancer treated with external beam radiation therapy (EBRT).Methods and Materials: Between January 2000 and January 2002, 224 patients (median age, 69 years; age range, 45–82 years) with biopsy-proven prostate cancer underwent endorectal MRI before high-dose (≥81Gy) EBRT. The value of multiple clinical and MRI variables in predicting prostate-specific antigen (PSA) relapse at 5 years was determined by use of univariate and multivariate stepwise Cox regression. Clinical variables included pretreatment PSA, clinical T stage, Gleason score, use of neoadjuvant hormonal therapy, and radiation dose. Magnetic resonance imaging variables, derived from retrospective consensus readings by two radiologists, were used to measure intraprostatic and extraprostatic tumor burden.Results: After a median follow-up of 67 months, PSA relapse developed in 37 patients (16.5%). The significant predictors of PSA relapse on univariate analysis were pretreatment PSA, clinical T stage, and multiple MRI variables, including MRI TN stage score; extracapsular extension (ECE) status; number of sextants involved by ECE, all lesions, or index (dominant) lesion; apical involvement; and diameter and volume of index lesion. Pretreatment PSA and ECE status were the only significant independent predictors on multivariate analysis (p < 0.05 for both). Extracapsular extension status was associated with the highest hazard ratio, 3.04; 5-year PSA relapse rates were 7% for no ECE, 20% for unilateral ECE, and 48% for bilateral ECE.Conclusions: Magnetic resonance imaging findings can be used to predict post-EBRT PSA relapse, with ECE status on MRI and pretreatment PSA being significant independent predictors of this endpoint.

Phase I Study of Daily Irinotecan as a Radiation Sensitizer for Locally Advanced Pancreatic Cancer - Corrected Proof

2010-01-29

Purpose: The study aimed to determine the maximum tolerated dose of daily irinotecan given with concomitant radiotherapy in patients with locally advanced adenocarcinoma of the pancreas.Methods and Materials: Between September 2000 and March 2008, 36 patients with histologically proven unresectable pancreas adenocarcinoma were studied prospectively. Irinotecan was administered daily, 1 to 2 h before irradiation. Doses were started at 6 mg/m2 per day and then escalated by increments of 2 mg/m2 every 3 patients. Radiotherapy was administered in 2-Gy fractions, 5 fractions per week, up to a total dose of 50 Gy to the tumor volume. Inoperability was confirmed by a surgeon involved in a multidisciplinary team. All images and responses were centrally reviewed by radiologists.Results: Thirty-six patients were enrolled over a period of 8 years through eight dose levels (6 mg/m2 to 20 mg/m2 per day). The maximum tolerated dose was determined to be 18 mg/m2 per day. The dose-limiting toxicities were nausea/vomiting, diarrhea, anorexia, dehydration, and hypokalemia. The median survival time was 12.6 months with a median follow-up of 53.8 months. The median progression-free survival time was 6.5 months, and 4 patients (11.4%) with very good responses could undergo surgery.Conclusions: The maximum tolerated dose of irinotecan is 18 mg/m2 per day for 5 weeks. Dose-limiting toxicities are mainly gastrointestinal. Even though efficacy was not the aim of this study, the results are very promising, with a median survival time of 12.6 months.

Outcome of Carotid Artery Stenting for Radiation-Induced Stenosis - Corrected Proof

2010-01-29

Purpose: Patients who have been irradiated at the neck have an increased risk of symptomatic stenosis of the carotid artery during follow-up. Carotid angioplasty and stenting (CAS) can be a preferable alternative treatment to carotid endarterectomy, which is associated with increased operative risks in these patients.Methods and Materials: We performed a prospective cohort study of 24 previously irradiated patients who underwent CAS for symptomatic carotid stenosis. We assessed periprocedural and nonprocedural events including transient ischemic attack (TIA), nondisabling stroke, disabling stoke, and death. Patency rates were evaluated on duplex ultrasound scans. Restenosis was defined as a stenosis of >50% at the stent location.Results: Periprocedural TIA rate was 8%, and periprocedural stroke (nondisabling) occurred in 4% of patients. After a mean follow-up of 3.3 years (range, 0.3–11.0 years), only one ipsilateral incident event (TIA) had occurred (4%). In 12% of patients, a contralateral incident event was present: one TIA (4%) and two strokes (12%, two disabling strokes). Restenosis was apparent in 17%, 33%, and 42% at 3, 12, and 24 months, respectively, although none of the patients with restenosed vessels became symptomatic. The length of the irradiation to CAS interval proved the only significant risk factor for restenosis.Conclusions: The results of CAS for radiation-induced carotid stenosis are favorable in terms of recurrence of cerebrovascular events at the CAS site.

Accurate Automatic Delineation of Heterogeneous Functional Volumes in Positron Emission Tomography for Oncology Applications - Corrected Proof

2010-01-29

Purpose: Accurate contouring of positron emission tomography (PET) functional volumes is now considered crucial in image-guided radiotherapy and other oncology applications because the use of functional imaging allows for biological target definition. In addition, the definition of variable uptake regions within the tumor itself may facilitate dose painting for dosimetry optimization.Methods and Materials: Current state-of-the-art algorithms for functional volume segmentation use adaptive thresholding. We developed an approach called fuzzy locally adaptive Bayesian (FLAB), validated on homogeneous objects, and then improved it by allowing the use of up to three tumor classes for the delineation of inhomogeneous tumors (3-FLAB). Simulated and real tumors with histology data containing homogeneous and heterogeneous activity distributions were used to assess the algorithm's accuracy.Results: The new 3-FLAB algorithm is able to extract the overall tumor from the background tissues and delineate variable uptake regions within the tumors, with higher accuracy and robustness compared with adaptive threshold (Tbckg) and fuzzy C-means (FCM). 3-FLAB performed with a mean classification error of less than 9% ± 8% on the simulated tumors, whereas binary-only implementation led to errors of 15% ± 11%. Tbckg and FCM led to mean errors of 20% ± 12% and 17% ± 14%, respectively. 3-FLAB also led to more robust estimation of the maximum diameters of tumors with histology measurements, with <6% standard deviation, whereas binary FLAB, Tbckg and FCM lead to 10%, 12%, and 13%, respectively.Conclusion: These encouraging results warrant further investigation in future studies that will investigate the impact of 3-FLAB in radiotherapy treatment planning, diagnosis, and therapy response evaluation.

Complications After Sphincter-Saving Resection in Rectal Cancer Patients According to Whether Chemoradiotherapy is Performed Before or After Surgery - Corrected Proof

2010-01-27

Purpose: The aim of the present study was to compare the influence of preoperative chemoradiotherapy (CRT) with postoperative CRT on the incidence and types of postoperative complications in rectal cancer patients who underwent sphincter-saving resection.Patients and Methods: We reviewed 285 patients who received preoperative CRT and 418 patients who received postoperative CRT between January 2000 and December 2006.Results: There was no between-group difference in age, gender, or cancer stage. In the pre-CRT group, the mean level of anastomosis from the anal verge was lower (3.5 ± 1.4 cm vs. 4.3 ± 1.7 cm, p < 0.001) and the rate of T4 lesion and temporary diverting ileostomy was higher than in the post-CRT group. Delayed anastomotic leakage and rectovaginal fistulae developed more frequently in the pre-CRT group than in the post-CRT group (3.9% vs. 1.2%, p = 0.020, 6.5% vs. 1.3%, p = 0.027, respectively). Small bowel obstruction (arising from radiation enteritis) requiring surgical intervention was more frequent in the post-CRT group (0% in the pre-CRT group vs. 1.4% in the post-CRT group, p = 0.042). Multivariate analysis identified preoperative CRT as an independent risk factor for fistulous complications (delayed anastomotic leakage, rectovaginal fistula, rectovesical fistula), and postoperative CRT as a risk factor for obstructive complications (anastomotic stricture, small bowel obstruction). The stoma-free rates were significantly lower in the pre-CRT group than in the post-CRT group (5-year stoma-free rates: 92.8% vs. 97.0%, p = 0.008).Conclusion: The overall postoperative complication rates were similar between the pre-CRT and the Post-CRT groups. However, the pattern of postoperative complications seen after sphincter- saving resection differed with reference to the timing of CRT.

Exeresis and Brachytherapy as Salvage Treatment for Local Recurrence After Conservative Treatment for Breast Cancer: Results of a Ten-Year Pilot Study - Corrected Proof

2010-01-27

Purpose: To analyze the long-term results of a pilot study assessing excision and brachytherapy as salvage treatment for local recurrence after conservative treatment of breast cancer.Methods and Materials: Between December 1990 and March 2001, 36 patients with breast-only recurrence less than 3 cm in diameter after conservative treatment for Stage I or II breast carcinoma were treated with local excision followed by high–dose rate brachytherapy implants (30 Gy in 12 fractions over a period of 5 days). No patient was lost to follow-up. Special attention was paid to local, regional, or distant recurrences; survival; cosmesis; and early and late side effects.Results: All patients completed treatment. During follow-up (range, 1–13 years), 8 patients presented metastases (2 regional and 6 distant) as their first site of failure, 1 had a differed local recurrence, and 1 died of the disease. Actuarial results at 10 years were as follows: local control, 89.4%; disease-free survival, 64.4%; and survival, 96.7%. Cosmetic results were satisfactory in 90.4%. No patient had Grade 3 or 4 early or late complications. Of the 11 patients followed up for at least 10 years, all but 1 still had their breast in place at the 10-year stage.Conclusions: High–dose rate brachytherapy is a safe, effective treatment for small-size, low-risk local recurrence after local excision in conservatively treated patients. The dose of 30 Gy of high–dose rate brachytherapy (12 fractions over a period of 5 days twice daily) was well tolerated. The excellent results support the use of breast preservation as salvage treatment in selected patients with local recurrence after conservative treatment for breast cancer.

Health-Related Quality of Life up to Six Years After 125I Brachytherapy for early-stage Prostate Cancer - Corrected Proof

2010-01-25

Purpose: Health-related quality of life (HRQOL) after prostate brachytherapy has been extensively described in published reports but hardly any long-term data are available. The aim of the present study was to prospectively assess long-term HRQOL 6 years after 125I prostate brachytherapy.Methods and Materials: A total of 127 patients treated with 125I brachytherapy for early-stage prostate cancer between December 2000 and June 2003 completed a HRQOL questionnaire at five time-points: before treatment and 1 month, 6 months, 1 year, and 6 years after treatment. The questionnaire included the RAND-36 generic health survey, the cancer-specific European Organization for Research and Treatment of Cancer core questionnaire (EORTCQLQ-C30), and the tumor-specific EORTC prostate cancer module (EORTC-PR25). A change in a score of ≥10 points was considered clinically relevant.Results: Overall, the HRQOL at 6 years after 125I prostate brachytherapy did not significantly differ from baseline. Although a statistically significant deterioration in HRQOL at 6 years was seen for urinary symptoms, bowel symptoms, pain, physical functioning, and sexual activity (p <.01), most changes were not clinically relevant. A statistically significant improvement at 6 years was seen for mental health, emotional functioning, and insomnia (p <.01). The only clinically relevant changes were seen for emotional functioning and sexual activity.Conclusion: This is the first study presenting prospective HRQOL data up to 6 years after 125I prostate brachytherapy. HRQOL scores returned to approximately baseline values at 1 year and remained stable up to 6 years after treatment. 125I prostate brachytherapy did not adversely affect patients' long-term HRQOL.

Intraoperative Radiotherapy as a Boost During Breast-Conserving Surgery Using Low-Kilovoltage X-Rays: The First 5 Years of Experience with a Novel Approach - Corrected Proof

2010-01-25

Purpose: Intraoperative radiotherapy (IORT) during breast-conserving surgery (BCS) has been recently introduced using different devices. We report the first 5 years of a single-center experience after introduction of a novel approach to deliver IORT as a tumor bed boost during BCS for breast cancer.Methods and Materials: A total of 155 breast cancers in 154 women (median age, 63 years; range, 30–83 years; T1/T2 = 100/55; N0/N+ = 108/47) were treated between February 2002 and December 2007 at the University Medical Center Mannheim, in whom IORT as tumor bed boost was applied using 50-kV X-rays (20 Gy) followed by 46–50 Gy whole-breast external-beam radiotherapy (EBRT). Chemotherapy, if indicated, was given before EBRT. The median interval between BCS plus IORT and EBRT was 40 days. Median follow-up was 34 months (maximum 80 months, 1 patient lost to follow-up). Overall survival and local relapse-free survival were calculated at 5 years using the Kaplan-Meier method. Seventy-nine patients were evaluated at 3-year follow-up for late toxicity according to the Late Effects in Normal Tissues–Subjective, Objective, Management, and Analytic system.Results: Ten patients died, 2 had in-breast relapse, and 8 developed distant metastases (5-year overall survival = 87.0%; 5-year local relapse-free survival = 98.5%). Grade 3 fibroses of the tumor bed were detected in 5% of the patients after 3 years. Skin toxicity was mild (telangiectases and hyperpigmentations in approximately 6% each).Conclusions: Intraoperative radiotherapy as a tumor bed boost during BCS for breast cancer using low-kilovoltage X-rays followed by EBRT yields low recurrence and toxicity rates.

Spot Scanning Proton Beam Therapy for Prostate Cancer: Treatment Planning Technique and Analysis of Consequences of Rotational and Translational Alignment Errors - Corrected Proof

2010-01-25

Purpose: Conventional proton therapy with passively scattered beams is used to treat a number of tumor sites, including prostate cancer. Spot scanning proton therapy is a treatment delivery means that improves conformal coverage of the clinical target volume (CTV). Placement of individual spots within a target is dependent on traversed tissue density. Errors in patient alignment perturb dose distributions. Moreover, there is a need for a rational planning approach that can mitigate the dosimetric effect of random alignment errors. We propose a treatment planning approach and then analyze the consequences of various simulated alignment errors on prostate treatments.Methods and Materials: Ten control patients with localized prostate cancer underwent treatment planning for spot scanning proton therapy. After delineation of the clinical target volume, a scanning target volume (STV) was created to guide dose coverage. Errors in patient alignment in two axes (rotational and yaw) as well as translational errors in the anteroposterior direction were then simulated, and dose to the CTV and normal tissues were reanalyzed.Results: Coverage of the CTV remained high even in the setting of extreme rotational and yaw misalignments. Changes in the rectum and bladder V45 and V70 were similarly minimal, except in the case of translational errors, where, as a result of opposed lateral beam arrangements, much larger dosimetric perturbations were observed.Conclusions: The concept of the STV as applied to spot scanning radiation therapy and as presented in this report leads to robust coverage of the CTV even in the setting of extreme patient misalignments.

Multidisciplinary Team Contributions Within a Dedicated Outpatient Palliative Radiotherapy Clinic: A Prospective Descriptive Study - Corrected Proof

2010-01-25

Purpose: Patients with bone metastases may experience pain, fatigue, and decreased mobility. Multiple medications for analgesia are often required, each with attendant side effects. Although palliative-intent radiotherapy (RT) is effective in decreasing pain, additional supportive care interventions may be overlooked. Our objective was to describe the feasibility of multidisciplinary assessment of patients with symptomatic bone metastases attending a dedicated outpatient palliative RT clinic.Methods and Materials: Consecutive patients referred for RT for painful bone metastases were screened for symptoms and needs relevant to their medications, nutritional intake, activities of daily living, and psychosocial and spiritual concerns from January 1 to December 31, 2007. Consultations by appropriate team members and resulting recommendations were collected prospectively. Patients who received RT were contacted by telephone 4 weeks later to assess symptom outcomes.Results: A total of 106 clinic visits by 82 individual patients occurred. As determined by screening form responses, the clinical Pharmacist, Occupational Therapist, Registered Dietician and Social Worker were consulted to provide assessments and recommendations within the time constraints presented by 1-day palliative RT delivery. In addition to pain relief, significant improvements in tiredness, depression, anxiety, drowsiness and overall well-being were reported at 4 weeks.Conclusions: Systematic screening of this population revealed previously unmet needs, addressed in the form of custom verbal and written recommendations. Multidisciplinary assessment is associated with a high number of recommendations and decreased symptom distress. Our findings lend strong support to the routine assessment by multiple supportive care professionals for patients with advanced cancer being considered for palliative RT.

Measurement of Neutron Dose Equivalent and its Dependence on Beam Configuration for a Passive Scattering Proton Delivery System - Corrected Proof

Xin Wang, Narayan Sahoo, Ronald X. Zhu, John R. Zullo, Michael T. Gillin — 2010-01-25

Purpose: To measure the neutron dose equivalent per therapeutic proton dose (H/D) in a passive scattering proton therapy system and study its dependence on the proton energy, aperture-to-isocenter distance, spread-out Bragg peak (SOBP) width, and field size.Methods and Materials: We performed four experiments of varying proton energies, aperture-to-isocenter distances, SOBP widths, and field sizes. Etched track detectors were used to measure the neutron dose equivalent at both an in-field (isocenter, beyond the protons' range) and out-of-field (30 cm lateral to the isocenter) location in air.Results: For a nonmodulated beam with all the protons stopping in the aperture and an aperture-to-isocenter distance of 30 cm, the H/D values measured at the isocenter were approximately 0.3 mSv/Gy for all snouts with a 100-MeV beam. The H/D values increased to 10.7, 14.5, and 15.1 mSv/Gy, respectively, for small, medium, and large snouts when the beam energy increased to 250 MeV. At the out-of-field location, H/D values increased from 0.1 to 2.7, 3.0, and 3.2 mSv/Gy, respectively, for small, medium, and large snouts. When the aperture-to-isocenter distance was changed from 10 to 40 cm, the H/D value at the isocenter dropped 70%. The H/D value doubled for the modulated beam relative to the nonmodulated beam. Open apertures reduced the neutrons produced in the nozzle, but increased those produced in the phantom.Conclusions: Our data showed that changes in the four factors studied affect the H/D value in predictable ways which permits an estimate of a patient's neutron exposure.

Toxicity of Head-and-Neck Radiation Therapy in Human Immunodeficiency Virus–Positive Patients - Corrected Proof

Nicholas J. Sanfilippo, James Mitchell, David Grew, Mark DeLacure — 2010-01-25

Purpose: To examine the acute morbidity of high dose head and neck RT and CRT in patients with infected with HIV.Methods and Materials: All HIV-positive patients who underwent radiation therapy for head and neck cancer in our department between 2004 and 2008 were reviewed. Treatment related data were examined. All treatments were delivered with megavoltage photon beams or electron beams. Patients were evaluated by an attending radiation oncologist for toxicity and response on a weekly basis during therapy and monthly after treatment in a multidisciplinary clinic. Acute toxicities were recorded using the Radiation Therapy and Oncology Group (RTOG) common toxicity criteria. Response to treatment was based on both physical exam as well as post-treatment imaging as indicated.Results: Thirteen patients who underwent RT with a diagnosis of HIV were identified. Median age was 53 years and median follow-up was 22 months. Twelve had squamous cell carcinoma and one had lymphoproliferative parotiditis. Median radiation dose was 66.4 Gy and median duration of treatment was 51 days. The median number of scheduled radiotherapy days missed was zero (range 0 to 7). One patient (8%) developed Grade 4 confluent moist desquamation. Eight patients (61%) developed Grade 3 toxicity.Conclusion: Based on our results, HIV-positive individuals appear to tolerate treatment for head and neck cancer, with toxicity similar to that in HIV-negative individuals.

A Novel Dose Constraint to Reduce Xerostomia in Head-and-Neck Cancer Patients Treated with Intensity-Modulated Radiotherapy - Corrected Proof

2010-01-25

Purpose: To investigate the predictors of incidence and duration of xerostomia (XT) based on parotid glands (PG), submandibular glands (SMG), and both glands taken as a whole organ (TG) in head-and-neck cancer patients treated with intensity-modulated radiotherapy.Methods and Materials: A prospective study was initiated in May 2003. Sixty-three head-and-neck patients (44 with nasopharynx cancer) were included in the analysis. Using the dose–volume histogram the PG, SMG, and TG mean doses were calculated. Unstimulated and stimulated salivary flow were measured and XT-related questionnaires were compiled before and at 3, 6, 12, 18, and 24 months after radiotherapy. Salivary gland toxicity was evaluated using the Radiation Therapy Oncology Group scale, and Grade ≥3 toxicity was used as the endpoint. The XT incidence was investigated according to descriptive statistics and univariate and multivariate analysis. The Bonferroni method was used for multiple comparison adjustment.Results: After a reduced flow at 3 months after radiotherapy, recovery of salivary flow was observed over time. Primary site and salivary gland mean doses and volumes were identified in univariate analysis as prognostic factors. Multivariate analysis confirmed that TG mean dose (p = 0.00066) and pretreatment stimulated salivary flow (p = 0.00420) are independent factors for predicting XT.Conclusion: The TG mean dose correlates with XT as assessed by Radiation Therapy Oncology Group criteria, salivary output, and XT-related questionnaires. Our results suggest that TG mean dose is a candidate dose constraint for reducing XT, requiring considerably more validation in non–nasopharyngeal cancer patients.

Lung Dose for Minimally Moving Thoracic Lesions Treated with Respiration Gating - Corrected Proof

2010-01-25

Purpose: To evaluate incidental doses to benign lung tissue for patients with minimally moving lung lesions treated with respiratory gating.Methods and Materials: Seventeen lung patient plans were studied retrospectively. Tumor motion was less than 5 mm in all cases. For each patient, mid-ventilation (MidVen) and mid-inhalation (MidInh) breathing phases were reconstructed. The MidInh phase was centered on the end-of-inhale (EOI) phase within a 30% gating window. Planning target volumes, heart, and spinal cord were delineated on the MidVen phase and transferred to the MidInh phase. Lungs were contoured separately on each phase. Intensity-modulated radiotherapy plans were generated on the MidVen phases. The plans were transferred to the MidInh phase, and doses were recomputed. The evaluation metric was based on dose indices, volume indices, generalized equivalent uniform doses, and mass indices for targets and critical structures. Statistical tests were used to establish the significance of the differences between the reference (MidVen) and compared (MidInh) dose distributions.Results: Statistical tests demonstrated that the indices evaluated for targets, cord, and heart differed by within 2.3%. The index differences in the lungs, however, are in excess of 6%, indicating the potentially achievable lung sparing and/or dose escalation.Conclusions: Respiratory gating is a clinical option for patients with minimally moving lung lesions treated at EOI. Gating will be more beneficial for larger tumors, since dose escalation in those cases will result in a larger increase in the tumor control probability.

Simultaneous Integrated Boost Intensity-Modulated Radiotherapy in Patients with High-Grade Gliomas - Corrected Proof

2010-01-25

Purpose: We analyzed outcomes of simultaneous integrated boost (SIB) intensity-modulated radiotherapy (IMRT) in patients with high-grade gliomas, compared with a literature review.Methods and Materials: Forty consecutive patients (WHO grade III, 14 patients; grade IV, 26 patients) treated with SIB-IMRT were analyzed. A dose of 2.0 Gy was delivered to the planning target volume with a SIB of 0.4 Gy to the gross tumor volume with a total dose of 60 Gy to the gross tumor volume and 50 Gy to the planning target volume in 25 fractions during 5 weeks. Twenty patients received temozolomide chemotherapy.Results: At a median follow-up of 13.4 months (range, 3.7–55.9 months), median survival was 14.8 months. One- and 2-year survival rates were 78% and 65%, respectively, for patients with grade III tumors and 56% and 31%, respectively, for patients with grade IV tumors. Age (≤50 vs. >50), grade (III vs. IV), subtype (astrocytoma vs. oligodendroglioma or mixed), and a Zubrod performance score (0–1 vs. >2) were predictive of survival. Of 25 (63%) patients who had recurrences, 17 patients had local failure, 9 patients had regional failure, and 1 patient had distant metastasis. Toxicities were acceptable.Conclusions: SIB-IMRT with the dose/fractionation used in this study is feasible and safe, with a survival outcome similar to the historical control. The shortening of treatment time by using SIB-IMRT may be of value, although further investigation is warranted to prove its survival advantage.

Differential Impact of Whole-Brain Radiotherapy Added to Radiosurgery for Brain Metastases - Corrected Proof

Doo-Sik Kong, Jung-Il Lee, Yong-Seok Im, Do-Hyun Nam, Kwan Park, Jong-Hyun Kim — 2010-01-25

Purpose: The authors investigated whether the addition of whole-brain radiotherapy (WBRT) to stereotactic radiosurgery (SRS) provided any therapeutic benefit according to recursive partitioning analysis (RPA) class.Methods and Materials: Two hundred forty-five patients with 1 to 10 metastases who underwent SRS between January 2002 and December 2007 were included in the study. Of those, 168 patients were treated with SRS alone and 77 patients received SRS followed by WBRT. Actuarial curves were estimated using the Kaplan-Meier method regarding overall survival (OS), distant brain control (DC), and local brain control (LC) stratified by RPA class. Analyses for known prognostic variables were performed using the Cox proportional hazards model.Results: Univariate and multivariate analysis revealed that control of the primary tumor, small number of brain metastases, Karnofsky performance scale (KPS) > 70, and initial treatment modalities were significant predictors for survival. For RPA class 1, SRS plus WBRT was associated with a longer survival time compared with SRS alone (854 days vs. 426 days, p = 0.042). The SRS plus WBRT group also showed better LC rate than did the SRS-alone group (p = 0.021), although they did not show a better DC rate (p = 0.079). By contrast, for RPA class 2 or 3, no significant difference in OS, LC, or DC was found between the two groups.Conclusions: These results suggest that RPA classification should determine whether or not WBRT is added to SRS. WBRT may be recommended to be added to SRS for patients in whom long-term survival is expected on the basis of RPA classification.

Clinical Applications of Volumetric Modulated Arc Therapy - Corrected Proof

Martha M. Matuszak, Di Yan, Inga Grills, Alvaro Martinez — 2010-01-25

Purpose: To present treatment planning case studies for several treatment sites for which volumetric modulated arc therapy (VMAT) could have a positive impact; and to share an initial clinical experience with VMAT for stereotactic body radiotherapy (SBRT).Methods and Materials: Four case studies are presented to show the potential benefit of VMAT compared with conformal and intensity-modulated radiotherapy (IMRT) techniques in pediatric cancer, bone marrow–sparing whole-abdominopelvic irradiation (WAPI), and SBRT of the lung and spine. Details of clinical implementation of VMAT for SBRT are presented. The VMAT plans are compared with conventional techniques in terms of dosimetric quality and delivery efficiency.Results: Volumetric modulated arc therapy reduced the treatment time of spine SBRT by 37% and improved isodose conformality. Conformal and VMAT techniques for lung SBRT had similar dosimetric quality, but VMAT had improved target coverage and took 59% less time to deliver, although monitor units were increased by 5%. In a complex pediatric pelvic example, VMAT reduced treatment time by 78% and monitor units by 25% compared with IMRT. A double-isocenter VMAT technique for WAPI can spare bone marrow while maintaining good delivery efficiency.Conclusions: Volumetric modulated arc therapy is a new technology that may benefit different patient populations, including pediatric cancer patients and those undergoing concurrent chemotherapy and WAPI. Volumetric modulated arc therapy has been used and shown to be beneficial for significantly improving delivery efficiency of lung and spine SBRT.

Single-Isocenter Frameless Intensity-Modulated Stereotactic Radiosurgery for Simultaneous Treatment of Multiple Brain Metastases: Clinical Experience - Corrected Proof

2010-01-21

Purpose: To describe our clinical experience using a unique single-isocenter technique for frameless intensity-modulated stereotactic radiosurgery (IM-SRS) to treat multiple brain metastases.Methods and Materials: Twenty-six patients with a median of 5 metastases (range, 2–13) underwent optically guided frameless IM-SRS using a single, centrally located isocenter. Median prescription dose was 18 Gy (range, 14–25). Follow-up magnetic resonance imaging (MRI) and clinical examination occurred every 2–4 months.Results: Median follow-up for all patients was 3.3 months (range, 0.2–21.3), with 20 of 26 patients (77%) followed up until their death. For the remaining 6 patients alive at the time of analysis, median follow-up was 14.6 months (range, 9.3–18.0). Total treatment time ranged from 9.0 to 38.9 minutes (median, 21.0). Actuarial 6- and 12-month overall survivals were 50% (95% confidence interval [C.I.], 31–70%) and 38% (95% C.I., 19–56%), respectively. Actuarial 6- and 12-month local control (LC) rates were 97% (95% C.I., 93–100%) and 83% (95% C.I., 71–96%), respectively. Tumors ≤1.5 cm had a better 6-month LC than those >1.5 cm (98% vs. 90%, p = 0.008). New intracranial metastatic disease occurring outside of the treatment volume was observed in 7 patients. Grade ≥3 toxicity occurred in 2 patients (8%).Conclusion: Frameless IM-SRS using a single-isocenter approach for treating multiple intracranial metastases can produce clinical outcomes that compare favorably with those of conventional SRS in a much shorter treatment time (<40 minutes). Given its faster treatment time, this technique is appealing to both patients and personnel in busy clinics.

Quality-of-Life-Adjusted Survival Analysis of Concurrent Chemo Radiotherapy for Locally Advanced (Nonmetastatic) Nasopharyngeal Cancer - Corrected Proof

Fei Gao, Joseph Wee, Hwee Bee Wong, David Machin — 2010-01-20

Purpose: To assess whether the benefits of adding cisplatin (CDDP) concurrent with radiotherapy, followed by adjuvant CDDP and fluorouracil, justifies the toxicity cost for nasopharyngeal cancer (NPC) using the quality-adjusted time without symptoms or toxicity (Q-TWiST) approach.Methods and Materials: One hundred seven patients treated with radiotherapy (RT) and 111 with concurrent chemotherapy and radiotherapy (CRT) were analyzed. The overall survival was divided into three health states: time on active treatment only, during which any subjective nonhematologic toxic event of grade >= 3 was reported; time without symptoms of disease relapse; or treatment and time following first disease RELapse. The relative advantage of CRT and RT was examined by conducting the analysis cumulatively at restriction times 3, 6, 24, 36, 48 months.Results: At 48 months, the improvement in disease-free survival was 14.4% for CRT, whereas that for overall survival was 18.9%. The differences in Q-TWiST were −0.4, −0.7, 0.1, 1.6, and 3.6 months at 3, 6, 24, 36, and 48 months, respectively, with positive differences favoring CRT. At 24 months, the difference in Q-TWiST began to favor CRT. At 36 months, CRT may be the preferred option from the patient's viewpoint if the time spent in the REL state is valued to be <0.83, with the value of perfect health being 1. Finally, Q-TWiST accumulated within 48 months indicated a significant advantage in quality-adjusted survival time for CRT (p = 0.020).Conclusion: Irrespective of how patients valued periods of toxicity and delayed disease progression, concurrent chemotherapy and radiotherapy offered NPC patients significantly more quality-adjusted survival than radiotherapy alone in the long term.

Expression of Bcl-2, p53, and MDM2 in Localized Prostate Cancer with Respect to the Outcome of Radical Radiotherapy Dose Escalation - Corrected Proof

2010-01-20

Purpose: Established prognostic factors in localized prostate cancer explain only a moderate proportion of variation in outcome. We analyzed tumor expression of apoptotic markers with respect to outcome in men with localized prostate cancer in two randomized controlled trials of radiotherapy dose escalation.Methods and Materials: Between 1995 and 2001, 308 patients with localized prostate cancer received neoadjuvant androgen deprivation and radical radiotherapy at our institution in one of two dose-escalation trials. The biopsy specimens in 201 cases were used to make a biopsy tissue microarray. We evaluated tumor expression of Bcl-2, p53, and MDM2 by immunohistochemistry with respect to outcome.Results: Median follow-up was 7 years, and 5-year freedom from biochemical failure (FFBF) was 70.4% (95% CI, 63.5–76.3%). On univariate analysis, expression of Bcl-2 (p < 0.001) and p53 (p = 0.017), but not MDM2 (p = 0.224), was significantly associated with FFBF. Expression of Bcl-2 remained significantly associated with FFBF (p = 0.001) on multivariate analysis, independently of T stage, Gleason score, initial prostate-specific antigen level, and radiotherapy dose. Seven-year biochemical control was 61% vs. 41% (p = 0.0122) for 74 Gy vs. 64 Gy, respectively, among patients with Bcl-2–positive tumors and 87% vs. 81% (p = 0.423) for 74 Gy vs. 64 Gy, respectively, among patients with Bcl-2–negative tumors. There was no statistically significant interaction between dose and Bcl-2 expression.Conclusions: Bcl-2 expression was a significant, independent determinant of biochemical control after neoadjuvant androgen deprivation and radical radiotherapy for prostate cancer. These data generate the hypothesis that Bcl-2 expression could be used to inform the choice of radiotherapy dose in individual patients.