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

Adjuvant Chemotherapy With or Without Pelvic Radiotherapy After Simultaneous Surgical Resection of Rectal Cancer with Liver Metastases: Analysis of Prognosis and Patterns of Recurrence - Corrected Proof

2012-02-01

Purpose: To investigate the outcomes of adjuvant chemotherapy (CT) or chemoradiotherapy (CRT) after simultaneous surgical resection in rectal cancer patients with liver metastases (LM).Materials and Methods: One hundred and eight patients receiving total mesorectal excision for rectal cancer and surgical resection for LM were reviewed. Forty-eight patients received adjuvant CRT, and 60 were administered CT alone. Recurrence patterns and prognosis were analyzed. Disease-free survival (DFS) and overall survival (OS) rates were compared between the CRT and CT groups. The inverse probability of the treatment-weighted (IPTW) method based on the propensity score was used to adjust for selection bias between the two groups.Results: At a median follow-up period of 47.7 months, 77 (71.3%) patients had developed recurrences. The majority of recurrences (68.8%) occurred in distant organs. By contrast, the local recurrence rate was only 4.7%. Median DFS and OS were not significantly different between the CRT and CT groups. After applying the IPTW method, we observed no significant differences in terms of DFS (hazard ratio [HR], 1.347; 95% confidence interval [CI], 0.759–2.392; p = 0.309) and OS (HR, 1.413; CI, 0.752–2.653; p = 0.282). Multivariate analyses showed that unilobar distribution of LM and normal preoperative carcinoembryonic antigen level (<6 mg/mL) were significantly associated with longer DFS and OS.Conclusions: The local recurrence rate after simultaneous resection of rectal cancer with LM was relatively low. DFS and OS rates were not different between the adjuvant CRT and CT groups. Adjuvant CRT may have a limited role in this setting. Further prospective randomized studies are required to evaluate optimal adjuvant treatment in these patients.

Similar Survival with Breast Conservation Therapy or Mastectomy in the Management of Young Women with Early-Stage Breast Cancer - Corrected Proof

2012-02-01

Purpose: To evaluate survival outcomes of young women with early-stage breast cancer treated with breast conservation therapy (BCT) or mastectomy, using a large, population-based database.Methods and Materials: Using the Surveillance, Epidemiology, and End Results (SEER) database, information was obtained for all female patients, ages 20 to 39 years old, diagnosed with T1–2 N0–1 M0 breast cancer between 1990 and 2007, who underwent either BCT (lumpectomy and radiation treatment) or mastectomy. Multivariable and matched pair analyses were performed to compare overall survival (OS) and cause-specific survival (CSS) of patients undergoing BCT and mastectomy.Results: A total of 14,764 women were identified, of whom 45% received BCT and 55% received mastectomy. Median follow-up was 5.7 years (range, 0.5–17.9 years). After we accounted for all patient and tumor characteristics, multivariable analysis found that BCT resulted in OS (hazard ratio [HR], 0.93; 95% confidence interval [CI], 0.83–1.04; p = 0.16) and CSS (HR, 0.93; CI, 0.83–1.05; p = 0.26) similar to that of mastectomy. Matched pair analysis, including 4,644 BCT and mastectomy patients, confirmed no difference in OS or CSS: the 5-, 10-, and15-year OS rates for BCT and mastectomy were 92.5%, 83.5%, and 77.0% and 91.9%, 83.6%, and 79.1%, respectively (p = 0.99), and the 5-, 10-, and 15-year CSS rates for BCT and mastectomy were 93.3%, 85.5%, and 79.9% and 92.5%, 85.5%, and 81.9%, respectively (p = 0.88).Conclusions: Our analysis of this population-based database suggests that young women with early-stage breast cancer have similar survival rates whether treated with BCT or mastectomy. These patients should be counseled appropriately regarding their treatment options and should not choose a mastectomy based on the assumption of improved survival.

Is Primary Prostate Cancer Treatment Influenced by Likelihood of Extraprostatic Disease? A Surveillance, Epidemiology and End Results Patterns of Care Study - Corrected Proof

2012-02-01

Purpose: To examine the patterns of primary treatment in a recent population-based cohort of prostate cancer patients, stratified by the likelihood of extraprostatic cancer as predicted by disease characteristics available at diagnosis.Methods and Materials: A total of 157,371 patients diagnosed from 2004 to 2008 with clinically localized and potentially curable (node-negative, nonmetastatic) prostate cancer, who have complete information on prostate-specific antigen, Gleason score, and clinical stage, were included. Patients with clinical T1/T2 disease were grouped into categories of <25%, 25–50%, and >50% likelihood of having extraprostatic disease using the Partin nomogram. Clinical T3/T4 patients were examined separately as the highest-risk group. Logistic regression was used to examine the association between patient group and receipt of each primary treatment, adjusting for age, race, year of diagnosis, marital status, Surveillance, Epidemiology and End Results database region, and county-level education. Separate models were constructed for primary surgery, external-beam radiotherapy (RT), and conservative management.Results: On multivariable analysis, increasing likelihood of extraprostatic disease was significantly associated with increasing use of RT and decreased conservative management. Use of surgery also increased. Patients with >50% likelihood of extraprostatic cancer had almost twice the odds of receiving prostatectomy as those with <25% likelihood, and T3–T4 patients had 18% higher odds. Prostatectomy use increased in recent years. Patients aged 76–80 years were likely to be managed conservatively, even those with a >50% likelihood of extraprostatic cancer (34%) and clinical T3–T4 disease (24%). The proportion of patients who received prostatectomy or conservative management was approximately 50% or slightly higher in all groups.Conclusions: There may be underutilization of RT in older prostate cancer patients and those with likely extraprostatic disease. Because more than half of prostate cancer patients do not consult with a radiation oncologist, a multidisciplinary consultation may affect the treatment decision-making process.

Long-Term Outcomes After High–Dose Postprostatectomy Salvage Radiation Treatment - Corrected Proof

2012-02-01

Purpose: To review the impact of high–dose radiotherapy (RT) in the postprostatectomy salvage setting on long-term biochemical control and distant metastases–free survival, and to identify clinical and pathologic predictors of outcomes.Methods and Materials: During 1988–2007, 285 consecutive patients were treated with salvage RT (SRT) after radical prostatectomy. All patients were treated with either three-dimensional conformal RT or intensity-modulated RT. Two hundred seventy patients (95%) were treated to a dose ≥66 Gy, of whom 205 (72%) received doses ≥70 Gy. Eighty-seven patients (31%) received androgen-deprivation therapy as a component of their salvage treatment. All clinical and pathologic records were reviewed to identify treatment risk factors and response.Results: The median follow-up time after SRT was 60 months. Seven-year actuarial prostate-specific antigen (PSA) relapse-free survival and distant metastases–free survival were 37% and 77%, respectively. Independent predictors of biochemical recurrence were vascular invasion (p < 0.01), negative surgical margins (p < 0.01), presalvage PSA level >0.4 ng/mL (p < 0.01), androgen-deprivation therapy (p = 0.03), Gleason score ≥7 (p = 0.02), and seminal vesicle involvement (p = 0.05). Salvage RT dose ≥70 Gy was not associated with improvement in biochemical control. A doubling time <3 months was the only independent predictor of metastatic disease (p < 0.01). There was a trend suggesting benefit of SRT dose ≥70 Gy in preventing clinical local failure in patients with radiographically visible local disease at time of SRT (7 years: 90% vs. 79.1%, p = 0.07).Conclusion: Salvage RT provides effective long-term biochemical control and freedom from metastasis in selected patients presenting with detectable PSA after prostatectomy. Androgen-deprivation therapy was associated with improvement in biochemical progression-free survival. Clinical local failures were rare but occurred most commonly in patients with greater burden of disease at time of SRT as reflected by either radiographic imaging or a greater PSA level. Salvage radiation doses ≥70 Gy may ultimately be most beneficial in these patients, but this needs to be further studied.

Critical Appraisal of Acuros XB and Anisotropic Analytic Algorithm Dose Calculation in Advanced Non-Small-Cell Lung Cancer Treatments - Corrected Proof

2012-02-01

Purpose: To assess the clinical impact of the Acuros XB algorithm (implemented in the Varian Eclipse treatment-planning system) in non-small-cell lung cancer (NSCLC) cases.Methods and Materials: A CT dataset of 10 patients presenting with advanced NSCLC was selected and contoured for planning target volume, lungs, heart, and spinal cord. Plans were created for 6-MV and 15-MV beams using three-dimensional conformal therapy, intensity-modulated therapy, and volumetric modulated arc therapy with RapidArc. Calculations were performed with Acuros XB and the Anisotropic Analytical Algorithm. To distinguish between differences coming from the different heterogeneity management and those coming from the algorithm and its implementation, all the plans were recalculated assigning Hounsfield Unit (HU) = 0 (Water) to the CT dataset.Results: Differences in dose distributions between the two algorithms calculated in Water were <0.5%. This suggests that the differences in the real CT dataset can be ascribed mainly to the different heterogeneity management, which is proven to be more accurate in the Acuros XB calculations. The planning target dose difference was stratified between the target in soft tissue, where the mean dose was found to be lower for Acuros XB, with a range of 0.4% ± 0.6% (intensity-modulated therapy, 6 MV) to 1.7% ± 0.2% (three-dimensional conformal therapy, 6 MV), and the target in lung tissue, where the mean dose was higher for 6 MV (from 0.2% ± 0.2% to 1.2% ± 0.5%) and lower for 15 MV (from 0.5% ± 0.5% to 2.0% ± 0.9%). Mean doses to organs at risk presented differences up to 3% of the mean structure dose in the worst case. No particular or systematic differences were found related to the various modalities. Calculation time ratios between calculation time for Acuros XB and the Anisotropic Analytical Algorithm were 7 for three-dimensional conformal therapy, 5 for intensity-modulated therapy, and 0.2 for volumetric modulated arc therapy with RapidArc.Conclusion: The availability of Acuros XB could improve patient dose estimation, increasing the data consistency of clinical trials.

Radiation Dose to the Brachial Plexus in Head-and-Neck Intensity-Modulated Radiation Therapy and Its Relationship to Tumor and Nodal Stage - Corrected Proof

2012-02-01

Purpose: The purpose of this retrospective study was to determine tumor factors contributing to brachial plexus (BP) dose in head-and-neck cancer (HNC) patients treated with intensity-modulated radiotherapy (IMRT) when the BP is routinely contoured as an organ at risk (OAR) for IMRT optimization.Methods and Materials: From 2004 to 2011, a total of 114 HNC patients underwent IMRT to a total dose of 69.96 Gy in 33 fractions, with the right and left BP prospectively contoured as separate OARs in 111 patients and the ipsilateral BP contoured in 3 patients (total, 225 BP). Staging category T4 and N2/3 disease were present in 34 (29.8%) and 74 (64.9%) patients, respectively. During IMRT optimization, the intent was to keep the maximum BP dose to ≤60 Gy, but prioritizing tumor coverage over achieving the BP constraints. BP dose parameters were compared with tumor and nodal stage.Results: With a median follow-up of 16.2 months, 43 (37.7%) patients had ≥24 months of follow-up with no brachial plexopathy reported. Mean BP volume was 8.2 ± 4.5 cm3. Mean BP maximum dose was 58.1 ± 12.2 Gy, and BP mean dose was 42.2 ± 11.3 Gy. The BP maximum dose was ≤60, ≤66, and ≤70 Gy in 122 (54.2%), 185 (82.2%), and 203 (90.2%) BP, respectively. For oropharynx, hypopharynx, and larynx sites, the mean BP maximum dose was 58.4 Gy and 63.4 Gy in T0–3 and T4 disease, respectively (p = 0.002). Mean BP maximum dose with N0/1 and N2/3 disease was 52.8 Gy and 60.9 Gy, respectively (p < 0.0001).Conclusions: In head-and-neck IMRT, dose constraints for the BP are difficult to achieve to ≤60 to 66 Gy with T4 disease of the larynx, hypopharynx, and oropharynx or N2/3 disease. The risk of brachial plexopathy is likely very small in HNC patients undergoing IMRT, although longer follow-up is required.

Effectiveness of Reirradiation for Painful Bone Metastases: A Systematic Review and Meta-Analysis - Corrected Proof

2012-02-01

Purpose: Reirradiation of painful bone metastases in nonresponders or patients with recurrent pain after initial response is performed in up to 42% of patients initially treated with radiotherapy. Literature on the effect of reirradiation for pain control in those patients is scarce. In this systematic review and meta-analysis, we quantify the effectiveness of reirradiation for achieving pain control in patients with painful bone metastases.Methods and Materials: A free text search was performed to identify eligible studies using the MEDLINE, EMBASE, and the Cochrane Collaboration library electronic databases. After study selection and quality assessment, a pooled estimate was calculated for overall pain response for reirradiation of metastatic bone pain.Results: Our literature search identified 707 titles, of which 10 articles were selected for systematic review and seven entered the meta-analysis. Overall study quality was mediocre. Of the 2,694 patients initially treated for metastatic bone pain, 527 (20%) patients underwent reirradiation. Overall, a pain response after reirradiation was achieved in 58% of patients (pooled overall response rate 0.58, 95% confidence interval = 0.49–0.67). There was a substantial between-study heterogeneity (I2 = 63.3%, p = 0.01) because of clinical and methodological differences between studies.Conclusions: Reirradiation of painful bone metastases is effective in terms of pain relief for a small majority of patients; approximately 40% of patients do not benefit from reirradiation. Although the validity of results is limited, this meta-analysis provides a comprehensive overview and the most quantitative estimate of reirradiation effectiveness to date.

Predicting Rectal and Bladder Overdose During the Course of Prostate Radiotherapy Using Dose–Volume Data from Initial Treatment Fractions - Corrected Proof

2012-02-01

Purpose: To evaluate whether information from the initial fractions can determine which patients are likely to consistently exceed their planning dose–volume constraints during the course of radiotherapy for prostate cancer.Methods and Materials: Ten patients with high-risk prostate cancer were treated with helical tomotherapy to a dose of 60 Gy in 20 fractions. The prostate, rectum, and bladder were recontoured on their daily megavoltage computed tomography scans and the dose was recalculated. The bladder and rectal volumes (in mL) receiving ≥100% and ≥70% of the prescribed dose in each fraction and in the original plans were recorded. A fraction for which the difference between planned and delivered was more than 2 mL was considered a volume failure. Similarly if the difference in the planned and delivered maximum dose (Dmax) was ≥1% for the rectum and bladder, the fraction was considered a dose failure. Each patient’s first 3 to 5 fractions were analyzed to determine if they correctly identified those patients who would consistently fail (i.e., ≥20% of fractions) during the course of their radiotherapy.Results: Six parameters were studied; the rectal volume (RV) and bladder volumes (BV) (in mL) received ≥100% and ≥70% of the prescribed dose and maximum dose to 2 mL of the rectum and bladder. This was given by RV100, RV70, BV100, BV70, RDmax, and BDmax, respectively. When more than 1 of the first 3 fractions exceed the planning constraint as defined, it accurately predicts consistent failures through the course of the treatment. This method is able to correctly identify the consistent failures about 80% (RV70, BV100, and RV100), 90% (BV70), and 100% (RDmax and BDmax) of the times.Conclusions: This study demonstrates the feasibility of a method accurately identifying patients who are likely to consistently exceed the planning constraints during the course of their treatment, using information from the first 3 to 5 fractions.

MRI-based Preplanning Using CT and MRI Data Fusion in Patients with Cervical Cancer Treated with 3D-based Brachytherapy: Feasibility and Accuracy Study - Corrected Proof

2012-02-01

Purpose: Magnetic resonance imaging (MRI)-assisted radiation treatment planning enables enhanced target contouring. The purpose of this study is to analyze the feasibility and accuracy of computed tomography (CT) and MRI data fusion for MRI-based treatment planning in an institution where an MRI scanner is not available in the radiotherapy department.Methods and Materials: The registration inaccuracy of applicators and soft tissue was assessed in 42 applications with CT/MRI data fusion. The absolute positional difference of the center of the applicators was measured in four different planes from the top of the tandem to the cervix. Any inaccuracy of registration of soft tissue in relation to the position of applicators was determined and dose–volume parameters for MRI preplans and for CT/MRI fusion plans with or without target and organs at risk (OAR) adaptation were evaluated.Results: We performed 6,132 measurements in 42 CT/MRI image fusions. Median absolute difference of the center of tandem on CT and MRI was 1.1 mm. Median distance between the center of the right ovoid on CT and MRI was 1.7 and 1.9 mm in the laterolateral and anteroposterior direction, respectively. Corresponding values for the left ovoid were 1.6 and 1.8 mm. Rotation of applicators was 3.1°. Median absolute difference in position of applicators in relation to soft tissue was 1.93, 1.50, 1.05, and 0.84 mm in the respective transverse planes, and 1.17, 1.28, 1.27, and 1.17 mm in selected angular directions. The dosimetric parameters for organs at risk on CT/MRI fusion plans without OAR adaptation were significantly impaired whereas the target coverage was not influenced. Planning without target adaptation led to overdosing of the target volume, especially high-risk clinical target volume — D90 88.2 vs. 83.1 (p < 0.05).Conclusions: MRI-based preplanning with consecutive CT/MRI data fusion can be safe and feasible, with an acceptable inaccuracy of soft tissue registration.

Sexual Function and the Use of Medical Devices or Drugs to Optimize Potency after Prostate Brachytherapy - Corrected Proof

2012-02-01

Purpose: Prospective evaluation of sexual outcomes after prostate brachytherapy with iodine-125 seeds as monotherapy at a tertiary cancer care center.Methods and Materials: Subjects were 129 men with prostate cancer with I-125 seed implants (prescribed dose, 145 Gy) without supplemental hormonal or external beam radiation therapy. Sexual function, potency, and bother were prospectively assessed at baseline and at 1, 4, 8, and 12 months using validated quality-of-life self-assessment surveys. Postimplant dosimetry values, including dose to 10% of the penile bulb (D10), D20, D33, D50, D75, D90, and penile volume receiving 100% of the prescribed dose (V100) were calculated.Results: At baseline, 56% of patients recorded having optimal erections; at 1 year, 62% of patients with baseline erectile function maintained optimal potency, 58% of whom with medically prescribed sexual aids or drugs. Variables associated with pretreatment-to-posttreatment decline in potency were time after implant (p = 0.04) and age (p = 0.01). Decline in urinary function may have been related to decline in potency. At 1 year, 69% of potent patients younger than 70 years maintained optimal potency, whereas 31% of patients older than 70 maintained optimal potency (p = 0.02). Diabetes was related to a decline in potency (p = 0.05), but neither smoking nor hypertension were. For patients with optimal potency at baseline, mean sexual bother scores had declined significantly at 1 year (p < 0.01). Sexual potency, sexual function, and sexual bother scores failed to correlate with any dosimetric variable tested.Conclusions: Erections firm enough for intercourse can be achieved at 1 year after treatment, but most men will require medical aids to optimize potency. Although younger men were better able to maintain erections firm enough for intercourse than older men, there was no correlation between potency, sexual function, or sexual bother and penile bulb dosimetry.

Outcome and Prognostic Factors in Endometrial Stromal Tumors: A Rare Cancer Network Study - Corrected Proof

2012-02-01

Purpose: To provide further understanding regarding outcome and prognostic factors of endometrial stromal tumors (EST).Methods and Materials: A retrospective analysis was performed on the records of 59 women diagnosed with EST and treated with curative intent between 1983 and 2007 in the framework of the Rare Cancer Network.Results: Endometrial stromal sarcomas (ESS) were found in 44% and undifferentiated ESS (UES) in 49% of the cases. In 7% the grading was unclear. Of the total number of patients, 33 had Stage I, 4 Stage II, 20 Stage III, and 1 presented with Stage IVB disease. Adjuvant chemotherapy was administered to 12 patients, all with UES. External-beam radiotherapy (RT) was administered postoperatively to 48 women. The median follow-up was 41.4 months. The 5-year overall survival (OS) rate was 96.2% and 64.8% for ESS and UES, respectively, with a corresponding 5-year disease-free survival (DFS) rate of 49.4% and 43.4%, respectively. On multivariate analysis, adjuvant RT was an independent prognostic factor for OS (p = 0.007) and DFS (p = 0.013). Locoregional control, DFS, and OS were significantly associated with age (≤60 vs. >60 years), grade (ESS vs. UES), and International Federation of Gynecology and Obstetrics stage (I–II vs. III–IV). Positive lymph node staging had an impact on OS (p < 0.001).Conclusion: The prognosis of ESS differed from that of UES. Endometrial stromal sarcomas had an excellent 5-year OS, whereas the OS in UES was rather low. However, half of ESS patients had a relapse. For this reason, adjuvant treatment such as RT should be considered even in low-grade tumors. Multicenter randomized studies are still warranted to establish clear guidelines.

In Vivo Dosimetry for Single-Fraction Targeted Intraoperative Radiotherapy (TARGIT) for Breast Cancer - Corrected Proof

2012-02-01

Purpose: In vivo dosimetry provides an independent check of delivered dose and gives confidence in the introduction or consistency of radiotherapy techniques. Single-fraction intraoperative radiotherapy of the breast can be performed with the Intrabeam compact, mobile 50 kV x-ray source (Carl Zeiss Surgical, Oberkochen, Germany). Thermoluminescent dosimeters (TLDs) can be used to estimate skin doses during these treatments.Methods and Materials: Measurements of skin doses were taken using TLDs for 72 patients over 3 years of clinical treatments. Phantom studies were also undertaken to assess the uncertainties resulting from changes in beam quality and backscatter conditions in vivo.Results: The mean measured skin dose was 2.9 ± 1.6 Gy, with 11% of readings higher than the prescription dose of 6 Gy, but none of these patients showed increased complications. Uncertainties due to beam hardening and backscatter reduction were small compared with overall accuracy.Conclusions: TLDs are a useful and effective method to measure in vivo skin doses in intraoperative radiotherapy and are recommended for the initial validation or any modification to the delivery of this technique. They are also an effective tool to show consistent and safe delivery on a more frequent basis or to determine doses to other critical structures as required.

Decreased Risk of Radiation Pneumonitis with Incidental Concurrent Use of Angiotensin-Converting Enzyme Inhibitors and Thoracic Radiation Therapy - Corrected Proof

Jordan Kharofa, Eric P. Cohen, Rade Tomic, Qun Xiang, Elizabeth Gore — 2012-02-01

Purpose: Angiotensin-converting enzyme (ACE) inhibitors have been shown to mitigate radiation-induced lung injury in preclinical models. The aim of this study was to evaluate whether ACE inhibitors decrease the risk of radiation pneumonitis in lung cancer patients receiving thoracic irradiation.Methods and Materials: Patients with Stage I through III small-cell and non-small-cell lung cancer treated definitively with radiation from 2004–2009 at the Clement J. Zablocki Veterans Affairs Medical Center were retrospectively reviewed. Acute pulmonary toxicity was quantified within 6 months of completion of treatment according to the Common Terminology Criteria for Adverse Events version 4. The use of ACE inhibitors, nonsteroidal anti-inflammatory drugs, inhaled glucocorticosteroids, statins, and angiotensin receptor blockers; dose–volume histogram parameters; and patient factors were assessed for association with Grade 2 or higher pneumonitis.Results: A total of 162 patients met the criteria for inclusion. The majority of patients had Stage III disease (64%) and received concurrent chemotherapy (61%). Sixty-two patients were identified as ACE inhibitor users (38%). All patients had acceptable radiation plans based on dose–volume histogram constraints (V20 [volume of lung receiving at least 20 Gy] ≤37% and mean lung dose ≤20 Gy) with the exception of 2 patients who did not meet both criteria. Grade 2 or higher pulmonary toxicity occurred in 12 patients (7.4%). The rate of Grade 2 or higher pneumonitis was lower in ACE inhibitor users vs. nonusers (2% vs. 11%, p = 0.032). Rates of Grade 2 or higher pneumonitis were significantly increased in patients aged greater than 70 years (16% vs. 2%, p = 0.005) or in whom V5 (volume of lung receiving at least 5 Gy) was 50% or greater (13% vs. 4%, p = 0.04). V10 (volume of lung receiving at least 10 Gy), V20, V30 (volume of lung receiving at least 30 Gy), and mean lung dose were not independently associated with Grade 2 or higher pneumonitis.Conclusion: ACE inhibitors may decrease the incidence of radiation pneumonitis in patients receiving thoracic radiation for lung cancer. These findings are consistent with preclinical evidence and should be prospectively evaluated.

Quality Assurance of Multifractionated Pelvic Interstitial Brachytherapy for Postoperative Recurrences of Cervical Cancers: A Prospective Study - Corrected Proof

2012-02-01

Purpose: To evaluate three-dimensional needle displacements during multifractionated interstitial brachytherapy (BT) for cervical cancers.Methods and Materials: Patients scheduled to undergo pelvic interstitial BT for postoperative and or postradiation vault recurrences were included from November 2009 to December 2010. All procedures were performed under spinal anesthesia. Postprocedure BT planning CT scans were obtained with patients in supine position with arms on the chest (interslice thickness of 3 mm). Thereafter, verification CT was repeated at every alternate fraction. Needle displacements were measured in reference to a relocatable bony point. The mean cranial, caudal, anteroposterior, and mediolateral displacements were recorded. Statistical significance of mean interfraction displacements was evaluated with Wilcoxon Test.Results: Twenty patients were included. Seventeen received boost BT (20 Gy/5 fractions/3 days) after external radiation, three received radical BT alone (36 Gy/9 fractions/5–8 days). An average of three scans (range, 2–3) were available per patient, and 357 needle displacements were analyzed. For the entire study cohort, the average of mean needle displacement was 2.5 mm (range, 0–7.4), 17.4 mm (range, 0–27.9), 1.7 mm (range, 0–6.7), 2.1 mm (range, 0–9.5), 1.7 mm (range, 0–9.3), and 0.6 mm (range, 0–7.8) in cranial, caudal, anterior, posterior, right, and left directions, respectively. The mean displacement in the caudal direction was higher between Days 1 and 2 than that between Days 2 and 3 (13.4 mm vs. 3.8 mm; p = 0.01). The average caudal displacements were no different between reirradiation and boost cohort (15.2 vs. 17.8 mm).Conclusions: Clinically significant caudal displacements occur during multifractionated pelvic brachytherapy. Optimal margins need to be incorporated while preplanning brachytherapy to account for interfraction displacements.

Sequence of Radiotherapy and Chemotherapy in Breast Cancer After Breast-Conserving Surgery - Corrected Proof

2012-02-01

Purpose: The optimal sequence of radiotherapy and chemotherapy in breast-conserving therapy is unknown.Methods and Materials: From 1983 through 2007, a total of 641 patients with 653 instances of breast-conserving therapy (BCT), received both chemotherapy and radiotherapy and are the basis of this analysis. Patients were divided into three groups. Groups A and B comprised patients treated before 2005, Group A radiotherapy first and Group B chemotherapy first. Group C consisted of patients treated from 2005 onward, when we had a fixed sequence of radiotherapy first, followed by chemotherapy.Results: Local control did not show any differences among the three groups. For distant metastasis, no difference was shown between Groups A and B. Group C, when compared with Group A, showed, on univariate and multivariate analyses, a significantly better distant metastasis–free survival. The same was noted for disease-free survival. With respect to disease-specific survival, no differences were shown on multivariate analysis among the three groups.Conclusion: Radiotherapy, as an integral part of the primary treatment of BCT, should be administered first, followed by adjuvant chemotherapy.

Prognostic Value of Subclassification Using MRI in the T4 Classification Nasopharyngeal Carcinoma Intensity-Modulated Radiotherapy Treatment - Corrected Proof

2012-02-01

Purpose: To subclassify patients with the T4 classification nasopharyngeal carcinoma (NPC), according to the seventh edition of the American Joint Committee on Cancer staging system, using magnetic resonance imaging (MRI), and to evaluate the prognostic value of subclassification after intensity-modulated radiotherapy (IMRT).Methods and Materials: A total of 140 patients who underwent MRI and were subsequently histologically diagnosed with nondisseminated classification T4 NPC received IMRT as their primary treatment and were included in this retrospective study. T4 patients were subclassified into two grades: T4a was defined as a primary nasopharyngeal tumor with involvement of the masticator space only; and T4b was defined as involvement of the intracranial region, cranial nerves, and/or orbit.Results: The 5-year overall survival (OS) rate and distant metastasis-free survival (DMFS) rate for T4a patients (82.5% and 87.0%, respectively), were significantly higher than for T4b patients (62.6% and 66.8%; p = 0.033 and p = 0.036, respectively). The T4a/b subclassification was an independent prognostic factor for OS (hazard ratio = 2.331, p = 0.032) and DMFS (hazard ratio = 2.602, p = 0.034), and had no significant effect on local relapse-free survival.Conclusions: Subclassification of T4 patients, as T4a or T4b, using MRI according to the site of invasion, has prognostic value for the outcomes of IMRT treatment in NPC.

The Number of High-Risk Factors and the Risk of Prostate Cancer–Specific Mortality After Brachytherapy: Implications for Treatment Selection - Corrected Proof

2012-02-01

Purpose: To determine whether an increasing number of high-risk factors is associated with higher prostate cancer–specific mortality (PCSM) among men treated with brachytherapy (BT)-based treatment, and whether supplemental therapy has an impact on this risk.Methods and Materials: We analyzed the cases of 2234 men with localized prostate cancer treated between 1991 and 2007 with low–dose rate BT monotherapy (n = 457) or BT with supplemental external-beam radiotherapy (EBRT, n = 229), androgen suppression therapy (AST, n = 424), or both (n = 1124). All men had at least one high-risk factor (prostate-specific antigen >20 ng/mL, biopsy Gleason score 8–10, or clinical stage ≥T2c). Competing-risks multivariable regressions were performed to determine whether the presence of at least two high-risk factors was associated with an increased risk of PCSM, with adjustment for age, comorbidity, and the type of supplemental treatment.Results: The median follow-up time was 4.3 years. The number of men with at least two high-risk factors was highest in the group treated with BT, EBRT, and AST (21%), followed by BT plus EBRT or AST (13%), and BT alone (8%) (ptrend < 0.001). The adjusted hazard ratio (AHR) for PCSM for those with at least two high-risk factors (as compared with one) was 4.8 (95% confidence interval [CI], 2.8–8.0; p < 0.001). The use of both supplemental EBRT and AST was associated with a decreased risk of PCSM (AHR 0.5; 95% CI, 0.2–0.9; p = 0.03) compared with BT alone. When the high-risk factors were analyzed separately, Gleason score 8–10 was most significantly associated with increased PCSM (AHR 6.2; 95% CI, 3.5–11.2; p < 0.001).Conclusions: Men with high-risk prostate adenocarcinoma treated with BT have decreased PCSM if they receive trimodailty therapy that includes EBRT and AST. This benefit is likely most important in men with multiple determinants of high risk.

Intensity-Modulated Radiotherapy is Associated with Improved Global Quality of Life Among Long-Term Survivors of Head-and-Neck Cancer - Corrected Proof

2012-02-01

Purpose: To compare the long-term quality of life among patients treated with and without intensity-modulated radiotherapy (IMRT) for head-and-neck cancer.Methods and Materials: The University of Washington Quality of Life instrument scores were reviewed for 155 patients previously treated with radiation therapy for locally advanced head-and-neck cancer. All patients were disease free and had at least 2 years of follow-up. Eighty-four patients (54%) were treated with IMRT. The remaining 71 patients (46%) were treated with three-dimensional conformal radiotherapy (3D CRT) by use of initial opposed lateral fields matched to a low anterior neck field.Results: The mean global quality of life scores were 67.5 and 80.1 for the IMRT patients at 1 and 2 years, respectively, compared with 55.4 and 57.0 for the 3D CRT patients, respectively (p < 0.001). At 1 year after the completion of radiation therapy, the proportion of patients who rated their global quality of life as “very good” or “outstanding” was 51% and 41% among patients treated by IMRT and 3DCRT, respectively (p = 0.11). At 2 years, the corresponding percentages increased to 73% and 49%, respectively (p < 0.001). On multivariate analysis accounting for sex, age, radiation intent (definitive vs. postoperative), radiation dose, T stage, primary site, use of concurrent chemotherapy, and neck dissection, the use of IMRT was the only variable independently associated with improved quality of life (p = 0.01).Conclusion: The early quality of life improvements associated with IMRT not only are maintained but apparently become more magnified over time. These data provide powerful evidence attesting to the long-term benefits of IMRT for head-and-neck cancer.

High-dose Helical Tomotherapy with Concurrent Full-dose Chemotherapy for Locally Advanced Pancreatic Cancer - Corrected Proof

2012-01-30

Purpose: To improve poor therapeutic outcome of current practice of chemoradiotherapy (CRT), high-dose helical tomotherapy (HT) with concurrent full-dose chemotherapy has been performed on patients with locally advanced pancreatic cancer (LAPC), and the results were analyzed.Methods and Materials: We retrospectively reviewed 39 patients with LAPC treated with radiotherapy using HT (median, 58.4 Gy; range, 50.8–59.9 Gy) and concomitant chemotherapy between 2006 and 2009. Radiotherapy was directed to the primary tumor with a 0.5-cm margin without prophylactic nodal coverage. Twenty-nine patients (79%) received full-dose (1000 mg/m2) gemcitabine-based chemotherapy during HT. After completion of CRT, maintenance chemotherapy was administered to 37 patients (95%).Results: The median follow-up was 15.5 months (range, 3.4–43.9) for the entire cohort, and 22.5 months (range, 12.0–43.9) for the surviving patients. The 1- and 2-year local progression-free survival rates were 82.1% and 77.3%, respectively. Eight patients (21%) were converted to resectable status, including 1 with a pathological complete response. The median overall survival and progression-free survival were 21.2 and 14.0 months, respectively. Acute toxicities were acceptable with no gastrointestinal (GI) toxicity higher than Grade 3. Severe late GI toxicity (≥Grade 3) occurred in 10 patients (26%); 1 treatment-related death from GI bleeding was observed.Conclusion: High-dose helical tomotherapy with concurrent full-dose chemotherapy resulted in improved local control and long-term survival in patients with LAPC. Future studies are needed to widen the therapeutic window by minimizing late GI toxicity.

Analysis of Local Control in Patients Receiving IMRT for Resected Pancreatic Cancers - Corrected Proof

2012-01-27

Purpose: Intensity-modulated radiotherapy (IMRT) is increasingly incorporated into therapy for pancreatic cancer. A concern regarding this technique is the potential for geographic miss and decreased local control. We analyzed patterns of first failure among patients treated with IMRT for resected pancreatic cancer.Methods and Materials: Seventy-one patients who underwent resection and adjuvant chemoradiation for pancreas cancer are included in this report. IMRT was used for all to a median dose of 50.4 Gy. Concurrent chemotherapy was 5-FU–based in 72% of patients and gemcitabine-based in 28%.Results: At median follow-up of 24 months, 49/71 patients (69%) had failed. The predominant failure pattern was distant metastases in 35/71 patients (49%). The most common site of metastases was the liver. Fourteen patients (19%) developed locoregional failure in the tumor bed alone in 5 patients, regional nodes in 4 patients, and concurrently with metastases in 5 patients. Median overall survival (OS) was 25 months. On univariate analysis, nodal status, margin status, postoperative CA 19-9 level, and weight loss during treatment were predictive for OS. On multivariate analysis, higher postoperative CA19-9 levels predicted for worse OS on a continuous basis (p < 0.01). A trend to worse OS was seen among patients with more weight loss during therapy (p = 0.06). Patients with positive nodes and positive margins also had significantly worse OS (HR for death 2.8, 95% CI 1.1–7.5; HR for death 2.6, 95% CI 1.1–6.2, respectively). Grade 3-4 nausea and vomiting was seen in 8% of patients. Late complication of small bowel obstruction occurred in 4 (6%) patients.Conclusions: This is the first comprehensive report of patterns of failure among patients treated with adjuvant IMRT for pancreas cancer. IMRT was not associated with an increase in local recurrences in our cohort. These data support the use of IMRT in the recently activated EORTC/US Intergroup/RTOG 0848 adjuvant pancreas trial.

Role of Early Postradiation Magnetic Resonance Imaging Scans in Children with Diffuse Intrinsic Pontine Glioma - Corrected Proof

2012-01-27

Purpose: To determine optimal timing of assessing postradiation radiographic response on magnetic resonance imaging (MRI) scans in pediatric patients with diffuse intrinsic pontine glioma (DIPG).Methods and Materials: Patients were treated on a prospective study at the National Cancer Institute (Protocol #06-C-0219) evaluating the effects of radiotherapy (RT). Standard RT was administered in standard fractionation over 6 weeks. Postradiation MRI scans were performed at 2 and 6–8 weeks.Results: Eleven patients with DIPG were evaluated. Median age was 6 years (range, 4–13 years). Patients were treated with external-beam RT to 55.8 Gy (n = 10) or 54 Gy (n = 1), with a gross tumor volume to planning target volume expansion of 1.8–2.0 cm. All patients received prescribed dose and underwent posttreatment MRI scans at 2 and 6–8 weeks. Pretreatment imaging revealed compression of fourth ventricle (n = 11); basilar artery encasement (n = 9); tumor extension outside the pons (n = 11); and tumor hemorrhage (n = 2). At the 2-week scan, basilar artery encasement improved in 7 of 9 patients, and extent of tumor was reduced in 5 of 11 patients. Fourth ventricle compression improved in 6 of 11 patients but worsened in 3 of 11 patients. Presumed necrosis was observed in 5 of 11 patients at 2 weeks and in 1 additional patient at 6–8 weeks. There was no significant difference in mean anteroposterior and transverse diameters of tumor between the 2- and 6–8-week time points. Six of 11 patients had increasing ventricular size, with no evidence of obstruction.Conclusions: There is no significant difference in tumor size of DIPG patients who have received standard RT when measured at 2 weeks vs. 6–8 weeks after RT. The majority of patients had the largest change in tumor size at the 2-week post-RT scan, with evolving changes documented on the 6–8-week scan. Six of 11 patients had progressive ventriculomegaly without obstruction, suggestive of communicating hydrocephalus. To the best of our knowledge, this is the first documentation of this phenomenon in this cohort of patients.

Pretreatment Staging Positron Emission Tomography/Computed Tomography in Patients With Inflammatory Breast Cancer Influences Radiation Treatment Field Designs - Corrected Proof

2012-01-27

Purpose: Positron emission tomography/computed tomography (PET/CT) is increasingly being utilized for staging of inflammatory breast cancer (IBC). The purpose of this study was to define how pretreatment PET/CT studies affected postmastectomy radiation treatment (PMRT) planning decisions for IBC.Methods and Materials: We performed a retrospective analysis of 62 patients diagnosed with IBC between 2004 and 2009, who were treated with PMRT in our institution and who had a staging PET/CT within 3 months of diagnosis. Patients received a baseline physical examination, staging mammography, ultrasonographic examination of breast and draining lymphatics, and chest radiography; most patients also had a bone scan (55 patients), liver imaging (52 patients), breast MRI (46 patients), and chest CT (25 patients). We compared how PET/CT findings affected PMRT, assuming that standard PMRT would target the chest wall, level III axilla, supraclavicular fossa, and internal mammary chain (IMC). Any modification of target volumes, field borders, or dose prescriptions was considered a change.Results: PET/CT detected new areas of disease in 27 of the 62 patients (44%). The areas of additional disease included the breast (1 patient), ipsilateral axilla (1 patient), ipsilateral supraclavicular (4 patients), ipsilateral infraclavicular (1 patient), ipsilateral IMC (5 patients), ipsilateral subpectoral (3 patients), mediastinal (8 patients), other distant/contralateral lymph nodes (15 patients), or bone (6 patients). One patient was found to have a non-breast second primary tumor. The findings of the PET/CT led to changes in PMRT in 11 of 62 patients (17.7%). These changes included additional fields in 5 patients, adjustment of fields in 2 patients, and higher doses to the supraclavicular fossa (2 patients) and IMC (5 patients).Conclusions: For patients with newly diagnosed IBC, pretreatment PET/CT provides important information concerning involvement of locoregional lymph nodes, mediastinal lymph nodes, and unsuspected sites of distant metastasis. This information is important in the design of radiotherapy treatment fields and, therefore, we recommend that PET/CT be a component of initial staging for IBC.

Frameless Angiogram-Based Stereotactic Radiosurgery for Treatment of Arteriovenous Malformations - Corrected Proof

2012-01-27

Purpose: Stereotactic radiosurgery (SRS) is an effective alternative to microsurgical resection or embolization for definitive treatment of arteriovenous malformations (AVMs). Digital subtraction angiography (DSA) is the gold standard for pretreatment diagnosis and characterization of vascular anatomy, but requires rigid frame (skull) immobilization when used in combination with SRS. With the advent of advanced proton and image-guided photon delivery systems, SRS treatment is increasingly migrating to frameless platforms, which are incompatible with frame-based DSA. Without DSA as the primary image, target definition may be less than optimal, in some cases precluding the ability to treat with a frameless system. This article reports a novel solution.Methods and Materials: Fiducial markers are implanted into the patient’s skull before angiography. Angiography is performed according to the standard clinical protocol, but, in contrast to the previous practice, without the rigid frame. Separate images of a specially designed localizer box are subsequently obtained. A target volume projected on DSA can be transferred to the localizer system in three dimensions, and in turn be transferred to multiple CT slices using the implanted fiducials. Combined with other imaging modalities, this “virtual frame” approach yields a highly precise treatment plan that can be delivered by frameless SRS technologies.Results: Phantom measurements for point and volume targets have been performed. The overall uncertainty of placing a point target to CT is 0.4 mm. For volume targets, deviation of the transformed contour from the target CT image is within 0.6 mm. The algorithm and software are robust. The method has been applied clinically, with reliable results.Conclusions: A novel and reproducible method for frameless SRS of AVMs has been developed that enables the use of DSA without the requirement for rigid immobilization. Multiple pairs of DSA can be used for better conformality. Further improvement, including using nonimplanted fiducials, is potentially feasible.

Evaluation of Field-in-Field Technique for Total Body Irradiation - Corrected Proof

Cem Onal, Aydan Sonmez, Gungor Arslan, Serhat Sonmez, Esma Efe, Ezgi Oymak — 2012-01-27

Purpose: To evaluate the clinical use of a field-in-field (FIF) technique for total body irradiation (TBI) using a treatment-planning system (TPS) and to verify TPS results with in vivo dose measurements using metal-oxide-semiconductor field-effect transistor (MOSFET) detectors.Methods and Materials: Clinical and dosimetric data of 10 patients treated with TBI were assessed. Certain radiation parameters were measured using homogenous and regular phantoms at an extended distance of 380 cm, and the results were compared with data from a conventional standard distance of 100 cm. Additionally, dosimetric validation of TPS doses was performed with a Rando phantom using manual calculations. A three-dimensional computed tomography plan was generated involving 18-MV photon beams with a TPS for both open-field and FIF techniques. The midline doses were measured at the head, neck, lung, umbilicus, and pelvis for both open-field and FIF techniques.Results: All patients received planned TBI using the FIF technique with 18-MV photon energies and 2 Gy b.i.d. on 3 consecutive days. The difference in tissue maximum ratios between the extended and conventional distances was <2%. The mean deviation of manual calculations compared with TPS data was +1.6% (range, 0.1–2.4%). A homogenous dose distribution was obtained with 18-MV photon beams using the FIF technique. The mean lung dose for the FIF technique was 79.2% (9.2 Gy; range, 8.8–9.7 Gy) of the prescribed dose. The MOSFET readings and TPS doses in the body were similar (percentage difference range, −0.5% to 2.5%) and slightly higher in the shoulder and lung (percentage difference range, 4.0–5.5%).Conclusion: The FIF technique used for TBI provides homogenous dose distribution and is feasible, simple, and spares time compared with more-complex techniques. The TPS doses were similar to the midline doses obtained from MOSFET readings.

Is There an Additional Value of 11C-Choline PET-CT to T2-weighted MRI Images in the Localization of Intraprostatic Tumor Nodules? - Corrected Proof

2012-01-27

Purpose: To investigate the additional value of 11C-choline positron emission tomography (PET)-computed tomography (CT) to T2-weighted (T2w) magnetic resonance imaging (MRI) for localization of intraprostatic tumor nodules.Methods and Materials: Forty-nine prostate cancer patients underwent T2w MRI and 11C-choline PET-CT before radical prostatectomy and extended lymphadenectomy. Tumor regions were outlined on the whole-mount histopathology sections and on the T2w MR images. Tumor localization was recorded in the basal, middle, and apical part of the prostate by means of an octant grid. To analyze 11C-choline PET-CT images, the same grid was used to calculate the standardized uptake values (SUV) per octant, after rigid registration with the T2w MR images for anatomic reference.Results: In total, 1,176 octants were analyzed. Sensitivity, specificity, and accuracy of T2w MRI were 33.5%, 94.6%, and 70.2%, respectively. For 11C-choline PET-CT, the mean SUVmax of malignant octants was significantly higher than the mean SUVmax of benign octants (3.69 ± 1.29 vs. 3.06 ± 0.97, p < 0.0001) which was also true for mean SUVmean values (2.39 ± 0.77 vs. 1.94 ± 0.61, p < 0.0001). A positive correlation was observed between SUVmean and absolute tumor volume (Spearman r = 0.3003, p = 0.0362). No correlation was found between SUVs and prostate-specific antigen, T-stage or Gleason score. The highest accuracy (61.1%) was obtained with a SUVmax cutoff of 2.70, resulting in a sensitivity of 77.4% and a specificity of 44.9%. When both modalities were combined (PET-CT or MRI positive), sensitivity levels increased as a function of SUVmax but at the cost of specificity. When only considering suspect octants on 11C-choline PET-CT (SUVmax ≥ 2.70) and T2w MRI, 84.7% of these segments were in agreement with the gold standard, compared with 80.5% for T2w MRI alone.Conclusions: The additional value of 11C-choline PET-CT next to T2w MRI in detecting tumor nodules within the prostate is limited.

Online Image-based Monitoring of Soft-tissue Displacements for Radiation Therapy of the Prostate - Corrected Proof

Jeffrey Schlosser, Kenneth Salisbury, Dimitre Hristov — 2012-01-27

Purpose: Emerging prolonged, hypofractionated radiotherapy regimens rely on high-dose conformality to minimize toxicity and thus can benefit from image guidance systems that continuously monitor target position during beam delivery. To address this need we previously developed, as a potential add-on device for existing linear accelerators, a novel telerobotic ultrasound system capable of real-time, soft-tissue imaging. Expanding on this capability, the aim of this work was to develop and characterize an image-based technique for real-time detection of prostate displacements.Methods and Materials: Image processing techniques were implemented on spatially localized ultrasound images to generate two parameters representing prostate displacements in real time. In a phantom and five volunteers, soft-tissue targets were continuously imaged with a customized robotic manipulator while recording the two tissue displacement parameters (TDPs). Variations of the TDPs in the absence of tissue displacements were evaluated, as was the sensitivity of the TDPs to prostate translations and rotations. Robustness of the approach to probe force was also investigated.Results: With 95% confidence, the proposed method detected in vivo prostate displacements before they exceeded 2.3, 2.5, and 2.8 mm in anteroposterior, superoinferior, and mediolateral directions. Prostate pitch was detected before exceeding 4.7° at 95% confidence. Total system time lag averaged 173 ms, mostly limited by ultrasound acquisition rate. False positives (FPs) in the absence of displacements did not exceed 1.5 FP events per 10 min of continuous in vivo imaging time.Conclusions: The feasibility of using telerobotic ultrasound for real-time, soft tissue–based monitoring of target displacements was confirmed in vivo. Such monitoring has the potential to detect small clinically relevant intrafractional variations of the prostate position during beam delivery.

Lhermitte Sign After Chemo-IMRT of Head-and-Neck Cancer: Incidence, Doses, and Potential Mechanisms - Corrected Proof

Daniel Pak, Karen Vineberg, Felix Feng, Randall K. Ten Haken, Avraham Eisbruch — 2012-01-27

Purpose: We have observed a higher rate of Lhermitte sign (LS) after chemo–intensity-modulated radiotherapy (IMRT) of head-and-neck cancer than the published rates after conventional radiotherapy. We hypothesized that the inhomogeneous spinal cord dose distributions produced by IMRT caused a “bath-and-shower” effect, characterized by low doses in the vicinity of high doses, reducing spinal cord tolerance.Methods and Materials: Seventy-three patients with squamous cell carcinoma of the oropharynx participated in a prospective study of IMRT concurrent with weekly carboplatin and paclitaxel. Of these, 15 (21%) reported LS during at least 2 consecutive follow-up visits. Mean dose, maximum dose, and partial volume and absolute volume (in milliliters) of spinal cord receiving specified doses (≥10 Gy, ≥20 Gy, ≥30 Gy, and ≥40 Gy), as well as the pattern of dose distributions at the “anatomic” spinal cord (from the base of the skull to the aortic arch) and “plan-related” spinal cord (from the top through the bottom of the planning target volumes), were compared between LS patients and 34 non-LS patients.Results: LS patients had significantly higher spinal cord mean doses, V30, V40, and absolute volumes receiving 30 Gy or more and 40 Gy or more compared with the non-LS patients (p < 0.05). The strongest predictors of LS were higher V40 and higher cord volumes receiving 40 Gy or more (p ≤ 0.007). There was no evidence of larger spinal cord volumes receiving low doses in the vicinity of higher doses (bath-and-shower effect) in LS compared with non-LS patients.Conclusions: Greater mean dose, V30, V40, and cord volumes receiving 30 Gy or more and 40 Gy or more characterized LS compared with non-LS patients. Bath-and-shower effects could not be validated in this study as a potential contributor to LS. The higher-than-expected rates of LS may be because of the specific concurrent chemotherapy agents or more accurate identification of LS in the setting of a prospective study.

Comparison of Heart and Coronary Artery Doses Associated with Intensity-Modulated Radiotherapy Versus Three-Dimensional Conformal Radiotherapy for Distal Esophageal Cancer - Corrected Proof

Thomas P. Kole, Osarhieme Aghayere, Jason Kwah, Ellen D. Yorke, Karyn A. Goodman — 2012-01-27

Purpose: To compare heart and coronary artery radiation exposure using intensity-modulated radiotherapy (IMRT) vs. four-field three-dimensional conformal radiotherapy (3D-CRT) treatment plans for patients with distal esophageal cancer undergoing chemoradiation.Methods and Materials: Nineteen patients with distal esophageal cancers treated with IMRT from March 2007 to May 2008 were identified. All patients were treated to 50.4 Gy with five-field IMRT plans. Theoretical 3D-CRT plans with four-field beam arrangements were generated. Dose–volume histograms of the planning target volume, heart, right coronary artery, left coronary artery, and other critical normal tissues were compared between the IMRT and 3D-CRT plans, and selected parameters were statistically evaluated using the Wilcoxon rank-sum test.Results: Intensity-modulated radiotherapy treatment planning showed significant reduction (p < 0.05) in heart dose over 3D-CRT as assessed by average mean dose (22.9 vs. 28.2 Gy) and V30 (24.8% vs. 61.0%). There was also significant sparing of the right coronary artery (average mean dose, 23.8 Gy vs. 35.5 Gy), whereas the left coronary artery showed no significant improvement (mean dose, 11.2 Gy vs. 9.2 Gy), p = 0.11. There was no significant difference in percentage of total lung volume receiving at least 10, 15, or 20 Gy or in the mean lung dose between the planning methods. There were also no significant differences observed for the kidneys, liver, stomach, or spinal cord. Intensity-modulated radiotherapy achieved a significant improvement in target conformity as measured by the conformality index (ratio of total volume receiving 95% of prescription dose to planning target volume receiving 95% of prescription dose), with the mean conformality index reduced from 1.56 to 1.30 using IMRT.Conclusions: Treatment of patients with distal esophageal cancer using IMRT significantly decreases the exposure of the heart and right coronary artery when compared with 3D-CRT. Long-term studies are necessary to determine how this will impact on development of coronary artery disease and other cardiac complications.

Glioblastoma Treatment: Bypassing the Toxicity of Platinum Compounds by Using Liposomal Formulation and Increasing Treatment Efficiency with Concomitant Radiotherapy - Corrected Proof

Gabriel Charest, Léon Sanche, David Fortin, David Mathieu, Benoit Paquette — 2012-01-27

Purpose: Treatments of glioblastoma with cisplatin or oxaliplatin only marginally improve the overall survival of patients and cause important side effects. To prevent adverse effects, improve delivery, and optimize the tumor response to treatment in combination with radiotherapy, a potential approach consists of incorporating the platinum agent in a liposome.Methods and Materials: In this study, cisplatin, oxaliplatin, carboplatin, Lipoplatin (the liposomal formulation of cisplatin), and Lipoxal (the liposomal formulation of oxaliplatin) were tested on F98 glioma orthotopically implanted in Fischer rats. The platinum compounds were administered by intracarotid infusion and were assessed for the ability to reduce toxicity, improve cancer cell uptake, and increase survival of animals when combined or not combined with radiotherapy.Results: The tumor uptake was 2.4-fold more important for Lipoxal than the liposome-free oxaliplatin. Lipoxal also improved the specificity of oxaliplatin as shown by a higher ratio of tumor to right hemisphere uptake. Surprisingly, Lipoplatin led to lower tumor uptake compared with cisplatin. However, Lipoplatin had the advantage of largely reducing the toxicity of cisplatin and allowed us to capitalize on the anticancer activity of this agent.Conclusion: Among the five platinum compounds tested, carboplatin showed the best increase in survival when combined with radiation for treatment of glioma implanted in Fischer rats.

High-Dose-Rate Brachytherapy and External-Beam Radiotherapy for Hormone-Naïve Low- and Intermediate-Risk Prostate Cancer: A 7-Year Experience - Corrected Proof

2012-01-27

Purpose: To report clinical outcomes and early and late complications in 264 hormone-naïve patients with low- and intermediate-risk prostate cancer treated with high-dose-rate brachytherapy (HDR-BT) in combination with external-beam radiotherapy (EBRT).Methods and Materials: Between February 2000 and July 2007, 264 patients underwent HDR-BT in combination with EBRT as a treatment for their low- to intermediate-risk prostate cancer. The HDR-BT was performed using ultrasound-based implantation. The total HDR-BT dose was 18 Gy in 3 fractions within 24 h, with a 6-h minimum interval. The EBRT started 2 weeks after HDR-BT and was delivered in 25 fractions of 1.8 Gy to 45 Gy within 5 weeks.Results: After a mean follow-up of 74.5 months, 4 patients (1.5%) showed prostate-specific antigen progression according to the American Society for Radiation Oncology definition and 8 patients (3%) according to the Phoenix definition. A biopsy-proven local recurrence was registered in 1 patient (0.4%), and clinical progression (bone metastases) was documented in 2 patients (0.7%). Seven-year actuarial freedom from biochemical failure was 97%, and 7-year disease-specific survival and overall survival were 100% and 91%, respectively. Toxicities were comparable to other series.Conclusions: Treatment with interstitial HDR-BT plus EBRT shows a low incidence of late complications and a favorable oncologic outcome after 7 years follow-up.

Projected Second Tumor Risk and Dose to Neurocognitive Structures After Proton Versus Photon Radiotherapy for Benign Meningioma - Corrected Proof

2012-01-27

Purpose: To calculated projected second tumor rates and dose to organs at risk (OAR) in patients with benign intracranial meningioma (BM), according to dosimetric comparisons between proton radiotherapy (PRT) and photon radiotherapy (XRT) treatment plans.Methods and Materials: Ten patients with BM treated at Massachusetts General Hospital during 2006–2010 with PRT were replanned with XRT (intensity-modulated or three-dimensional conformal radiotherapy), optimizing dose to the tumor while sparing OAR. Total dose was 54 Gy in 1.8 Gy per fraction for all plans. We calculated equivalent uniform doses, normal tissue complication probabilities, and whole brain–based estimates of excess risk of radiation-associated intracranial second tumors.Results: Excess risk of second tumors was significantly lower among PRT compared with XRT plans (1.3 vs. 2.8 per 10,000 patients per year, p < 0.002). Mean equivalent uniform doses were lower among PRT plans for the whole brain (19.0 vs. 22.8 Gy, p < 0.0001), brainstem (23.8 vs. 35.2 Gy, p = 0.004), hippocampi (left, 13.5 vs. 25.6 Gy, p < 0.0001; right, 7.6 vs. 21.8 Gy, p = 0.001), temporal lobes (left, 25.8 vs. 34.6 Gy, p = 0.007; right, 25.8 vs. 32.9 Gy, p = 0.008), pituitary gland (29.2 vs. 37.0 Gy, p = 0.047), optic nerves (left, 28.5 vs. 33.8 Gy, p = 0.04; right, 25.1 vs. 31.1 Gy, p = 0.07), and cochleas (left, 12.2 vs. 15.8 Gy, p = 0.39; right,1.5 vs. 8.8 Gy, p = 0.01). Mean normal tissue complication probability was <1% for all structures and not significantly different between PRT and XRT plans.Conclusions: Compared with XRT, PRT for BM decreases the risk of RT-associated second tumors by half and delivers significantly lower doses to neurocognitive and critical structures of vision and hearing.

A Computational Model of Cellular Response to Modulated Radiation Fields - Corrected Proof

2012-01-27

Purpose: To develop a model to describe the response of cell populations to spatially modulated radiation exposures of relevance to advanced radiotherapies.Materials and Methods: A Monte Carlo model of cellular radiation response was developed. This model incorporated damage from both direct radiation and intercellular communication including bystander signaling. The predictions of this model were compared to previously measured survival curves for a normal human fibroblast line (AGO1522) and prostate tumor cells (DU145) exposed to spatially modulated fields.Results: The model was found to be able to accurately reproduce cell survival both in populations which were directly exposed to radiation and those which were outside the primary treatment field. The model predicts that the bystander effect makes a significant contribution to cell killing even in uniformly irradiated cells. The bystander effect contribution varies strongly with dose, falling from a high of 80% at low doses to 25% and 50% at 4 Gy for AGO1522 and DU145 cells, respectively. This was verified using the inducible nitric oxide synthase inhibitor aminoguanidine to inhibit the bystander effect in cells exposed to different doses, which showed significantly larger reductions in cell killing at lower doses.Conclusions: The model presented in this work accurately reproduces cell survival following modulated radiation exposures, both in and out of the primary treatment field, by incorporating a bystander component. In addition, the model suggests that the bystander effect is responsible for a significant portion of cell killing in uniformly irradiated cells, 50% and 70% at doses of 2 Gy in AGO1522 and DU145 cells, respectively. This description is a significant departure from accepted radiobiological models and may have a significant impact on optimization of treatment planning approaches if proven to be applicable in vivo.

TAT-Mediated Delivery of Tousled Protein to Salivary Glands Protects Against Radiation-Induced Hypofunction - Corrected Proof

2012-01-27

Purpose: Patients treated with radiotherapy for head-and-neck cancer invariably suffer its deleterious side effect, xerostomia. Salivary hypofunction ensuing from the irreversible destruction of glands is the most common and debilitating oral complication affecting patients undergoing regional radiotherapy. Given that the current management of xerostomia is palliative and ineffective, efforts are now directed toward preventive measures to preserve gland function. The human homolog of Tousled protein, TLK1B, facilitates chromatin remodeling at DNA repair sites and improves cell survival against ionizing radiation (IR). Therefore, we wanted to determine whether a direct transfer of TLK1B protein to rat salivary glands could protect against IR-induced salivary hypofunction.Methods: The cell-permeable TAT-TLK1B fusion protein was generated. Rat acinar cell line and rat salivary glands were pretreated with TAT peptide or TAT-TLK1B before IR. The acinar cell survival in vitro and salivary function in vivo were assessed after radiation.Results: We demonstrated that rat acinar cells transduced with TAT-TLK1B were more resistant to radiation (D0 = 4.13 ± 1.0 Gy; α/β = 0 Gy) compared with cells transduced with the TAT peptide (D0 = 4.91 ± 1.0 Gy; α/β = 20.2 Gy). Correspondingly, retroductal instillation of TAT-TLK1B in rat submandibular glands better preserved salivary flow after IR (89%) compared with animals pretreated with Opti-MEM or TAT peptide (31% and 39%, respectively; p < 0.01).Conclusions: The results demonstrate that a direct transfer of TLK1B protein to the salivary glands effectively attenuates radiation-mediated gland dysfunction. Prophylactic TLK1B-protein therapy could benefit patients undergoing radiotherapy for head-and-neck cancer.

Treatment Outcome of Medium-Dose-Rate Intracavitary Brachytherapy for Carcinoma of the Uterine Cervix: Comparison with Low-Dose-Rate Intracavitary Brachytherapy - Corrected Proof

2012-01-27

Purpose: To evaluate and compare the efficacy of medium-dose-rate (MDR) and low-dose-rate (LDR) intracavitary brachytherapy (ICBT) for uterine cervical cancer.Methods and Materials: We evaluated 419 patients with squamous cell carcinoma of the cervix who were treated by radical radiotherapy with curative intent at Tokyo Women’s Medical University from 1969 to 1999. LDR was used from 1969 to 1986, and MDR has been used since July 1987. When compared with LDR, fraction dose was decreased and fraction size was increased (1 or 2 fractions) for MDR to make the total dose of MDR equal to that of LDR. In general, the patients received a total dose of 60 to 70 Gy at Point A with external beam radiotherapy combined with brachytherapy according to the International Federation of Gynecology and Obstetrics stage. In the LDR group, 32 patients had Stage I disease, 81 had Stage II, 182 had Stage III, and 29 had Stage IVA; in the MDR group, 9 patients had Stage I disease, 19 had Stage II, 55 had Stage III, and 12 had Stage IVA.Results: The 5-year overall survival rates for Stages I, II, III, and IVA in the LDR group were 78%, 72%, 55%, and 34%, respectively. In the MDR group, the 5-year overall survival rates were 100%, 68%, 52%, and 42%, respectively. No significant statistical differences were seen between the two groups. The actuarial rates of late complications Grade 2 or greater at 5 years for the rectum, bladder, and small intestine in the LDR group were 11.1%, 5.8%, and 2.0%, respectively. The rates for the MDR group were 11.7%, 4.2%, and 2.6%, respectively, all of which were without statistical differences.Conclusion: These data suggest that MDR ICBT is effective, useful, and equally as good as LDR ICBT in daytime (about 5 hours) treatments of patients with cervical cancer.

Setup Variations in Radiotherapy of Anal Cancer: Advantages of Target Volume Reduction Using Image-Guided Radiation Treatment - Corrected Proof

2012-01-27

Purpose: To define setup variations in the radiation treatment (RT) of anal cancer and to report the advantages of image-guided RT (IGRT) in terms of reduction of target volume and treatment-related side effects.Methods and Materials: Twelve consecutive patients with anal cancer treated by combined chemoradiation by use of helical tomotherapy from March 2007 to November 2008 were selected. With patients immobilized and positioned in place, megavoltage computed tomography (MVCT) scans were performed before each treatment and were automatically registered to planning CT scans. Patients were shifted per the registration data and treated. A total of 365 MVCT scans were analyzed. The primary site received a median dose of 55 Gy. To evaluate the potential dosimetric advantage(s) of IGRT, cases were replanned according to Radiation Therapy Oncology Group 0529, with and without adding recommended setup variations from the current study.Results: Significant setup variations were observed throughout the course of RT. The standard deviations for systematic setup correction in the anterior–posterior (AP), lateral, and superior–inferior (SI) directions and roll rotation were 1.1, 3.6, and 3.2 mm, and 0.3°, respectively. The average random setup variations were 3.8, 5.5, and 2.9 mm, and 0.5°, respectively. Without daily IGRT, margins of 4.9, 11.1, and 8.5 mm in the AP, lateral, and SI directions would have been needed to ensure that the planning target volume (PTV) received ≥95% of the prescribed dose. Conversely, daily IGRT required no extra margins on PTV and resulted in a significant reduction of V15 and V45 of intestine and V10 of pelvic bone marrow. Favorable toxicities were observed, except for acute hematologic toxicity.Conclusions: Daily MVCT scans before each treatment can effectively detect setup variations and thereby reduce PTV margins in the treatment of anal cancer. The use of concurrent chemotherapy and IGRT provided favorable toxicities, except for acute hematologic toxicity.

Personalized Assessment of kV Cone Beam Computed Tomography Doses in Image-guided Radiotherapy of Pediatric Cancer Patients - Corrected Proof

Yibao Zhang, Yulong Yan, Ravinder Nath, Shanglian Bao, Jun Deng — 2012-01-27

Purpose: To develop a quantitative method for the estimation of kV cone beam computed tomography (kVCBCT) doses in pediatric patients undergoing image-guided radiotherapy.Methods and Materials: Forty-two children were retrospectively analyzed in subgroups of different scanned regions: one group in the head-and-neck and the other group in the pelvis. Critical structures in planning CT images were delineated on an Eclipse treatment planning system before being converted into CT phantoms for Monte Carlo simulations. A benchmarked EGS4 Monte Carlo code was used to calculate three-dimensional dose distributions of kVCBCT scans with full-fan high-quality head or half-fan pelvis protocols predefined by the manufacturer. Based on planning CT images and structures exported in DICOM RT format, occipital-frontal circumferences (OFC) were calculated for head-and-neck patients using DICOMan software. Similarly, hip circumferences (HIP) were acquired for the pelvic group. Correlations between mean organ doses and age, weight, OFC, and HIP values were analyzed with SigmaPlot software suite, where regression performances were analyzed with relative dose differences (RDD) and coefficients of determination (R2).Results: kVCBCT-contributed mean doses to all critical structures decreased monotonically with studied parameters, with a steeper decrease in the pelvis than in the head. Empirical functions have been developed for a dose estimation of the major organs at risk in the head and pelvis, respectively. If evaluated with physical parameters other than age, a mean RDD of up to 7.9% was observed for all the structures in our population of 42 patients.Conclusions: kVCBCT doses are highly correlated with patient size. According to this study, weight can be used as a primary index for dose assessment in both head and pelvis scans, while OFC and HIP may serve as secondary indices for dose estimation in corresponding regions. With the proposed empirical functions, it is possible to perform an individualized quantitative dose assessment of kVCBCT scans.

Long-Term Results of Conformal Radiotherapy for Progressive Airway Amyloidosis - Corrected Proof

2012-01-23

Purpose: To evaluate the efficacy of conformal external beam radiotherapy (RT) for local control of progressive airway amyloidosis.Methods and Materials: We conducted a retrospective review of patients with biopsy-proven progressive airway amyloidosis treated with conformal RT between 2000 and 2006 at Boston Medical Center. The patients were evaluated for performance status and pulmonary function, with computed tomography and endoscopy after RT compared with the pretreatment studies. Local control was defined as the lack of progression of airway wall thickening on computed tomography imaging and stable endobronchial deposits by endoscopy.Results: A total of 10 symptomatic airway amyloidosis patients (3 laryngeal and 7 tracheobronchial) received RT to a median total dose of 20 Gy in 10 fractions within 2 weeks. At a median follow-up of 6.7 years (range, 1.5–10.3), 8 of the 10 patients had local control. The remaining 2 patients underwent repeat RT 6 and 8.4 months after initial RT, 1 for persistent bronchial obstruction and 1 for progression of subglottic amyloid disease with subsequent disease control. The Eastern Cooperative Oncology Group performance status improved at a median of 18 months after RT compared with the baseline values, from a median score of 2 to a median of 1 (p = .035). Airflow (forced expiratory volume in 1 second) measurements increased compared with the baseline values at each follow-up evaluation, reaching a 10.7% increase (p = .087) at the last testing (median duration, 64.8 months). Acute toxicity was limited to Grade 1-2 esophagitis, occurring in 40% of patients. No late toxicity was observed.Conclusions: RT prevented progressive amyloid deposition in 8 of 10 patients, resulting in a marginally increased forced expiratory volume in 1 second, and improved functional capacity, without late morbidity.

Oxidative Stress Mediates Radiation Lung Injury by Inducing Apoptosis - Corrected Proof

Yu Zhang, Xiuwu Zhang, Zahid N. Rabbani, Isabel L. Jackson, Zeljko Vujaskovic — 2012-01-23

Purpose: Apoptosis in irradiated normal lung tissue has been observed several weeks after radiation. However, the signaling pathway propagating cell death after radiation remains unknown.Methods and Materials: C57BL/6J mice were irradiated with 15 Gy to the whole thorax. Pro-apoptotic signaling was evaluated 6 weeks after radiation with or without administration of AEOL10150, a potent catalytic scavenger of reactive oxygen and nitrogen species.Results: Apoptosis was observed primarily in type I and type II pneumocytes and endothelium. Apoptosis correlated with increased PTEN expression, inhibition of downstream PI3K/AKT signaling, and increased p53 and Bax protein levels. Transforming growth factor-β1, Nox4, and oxidative stress were also increased 6 weeks after radiation. Therapeutic administration of AEOL10150 suppressed pro-apoptotic signaling and dramatically reduced the number of apoptotic cells.Conclusion: Increased PTEN signaling after radiation results in apoptosis of lung parenchymal cells. We hypothesize that upregulation of PTEN is influenced by Nox4-derived oxidative stress. To our knowledge, this is the first study to highlight the role of PTEN in radiation-induced pulmonary toxicity.

Image-guided Radiotherapy for Left-sided Breast Cancer Patients: Geometrical Uncertainty of the Heart - Corrected Proof

Rajko Topolnjak, Gerben R. Borst, Jasper Nijkamp, Jan-Jakob Sonke — 2012-01-23

Purpose: To quantify the geometrical uncertainties for the heart during radiotherapy treatment of left-sided breast cancer patients and to determine and validate planning organ at risk volume (PRV) margins.Methods and Materials: Twenty-two patients treated in supine position in 28 fractions with regularly acquired cone-beam computed tomography (CBCT) scans for offline setup correction were included. Retrospectively, the CBCT scans were reconstructed into 10-phase respiration correlated four-dimensional scans. The heart was registered in each breathing phase to the planning CT scan to establish the respiratory heart motion during the CBCT scan (σresp). The average of the respiratory motion was calculated as the heart displacement error for a fraction. Subsequently, the systematic (Σ), random (σ), and total random errors of the heart position were calculated. Based on the errors a PRV margin for the heart was calculated to ensure that the maximum heart dose (Dmax) is not underestimated in at least 90% of the cases (Mheart = 1.3Σ-0.5σtot). All analysis were performed in left-right (LR), craniocaudal (CC), and anteroposterior (AP) directions with respect to both online and offline bony anatomy setup corrections. The PRV margin was validated by accumulating the dose to the heart based on the heart registrations and comparing the planned PRV Dmax to the accumulated heart Dmax.Results: For online setup correction, the cardiac geometrical uncertainties and PRV margins were ∑ = 2.2/3.2/2.1 mm, σ = 2.1/2.9/1.4 mm, and Mheart = 1.6/2.3/1.3 mm for LR/CC/AP, respectively. For offline setup correction these were ∑ = 2.4/3.7/2.2 mm, σ = 2.9/4.1/2.7 mm, and Mheart = 1.6/2.1/1.4 mm. Cardiac motion induced by breathing was σresp = 1.4/2.9/1.4 mm for LR/CC/AP. The PRV Dmax underestimated the accumulated heart Dmax for 9.1% patients using online and 13.6% patients using offline bony anatomy setup correction, which validated that PRV margin size was adequate.Conclusion: Considerable cardiac position variability relative to the bony anatomy was observed in breast cancer patients. A PRV margin can be used during treatment planning to take these uncertainties into account.

Monochromatic Minibeams Radiotherapy: From Healthy Tissue-sparing Effect Studies Toward First Experimental Glioma Bearing Rats Therapy - Corrected Proof

2012-01-23

Purpose: The purpose of this study was to evaluate high-dose single fraction delivered with monochromatic X-rays minibeams for the radiotherapy of primary brain tumors in rats.Methods and Materials: Two groups of healthy rats were irradiated with one anteroposterior minibeam incidence (four minibeams, 123 Gy prescribed dose at 1 cm depth in the brain) or two interleaved incidences (54 Gy prescribed dose in a 5 × 5 × 4.8 mm3 volume centered in the right hemisphere), respectively. Magnetic resonance imaging (MRI) follow-up was performed over 1 year. T2-weighted (T2w) images, apparent diffusion coefficient (ADC), and blood vessel permeability maps were acquired. F98 tumor bearing rats were also irradiated with interleaved minibeams to achieve a homogeneous dose of 54 Gy delivered to an 8 × 8 × 7.8 mm3 volume centered on the tumor. Anatomic and functional MRI follow-up was performed every 10 days after irradiation. T2w images, ADC, and perfusion maps were acquired.Results: All healthy rats were euthanized 1 year after irradiation without any clinical alteration visible by simple examination. T2w and ADC measurements remain stable for the single incidence irradiation group. Localized Gd-DOTA permeability, however, was observed 9 months after irradiation for the interleaved incidences group.The survival time of irradiated glioma bearing rats was significantly longer than that of untreated animals (49 ± 12.5 days versus 23.3 ± 2 days, p < 0.001). The tumoral cerebral blood flow and blood volume tend to decrease after irradiation.Conclusions: This study demonstrates the sparing effect of minibeams on healthy tissue. The increased life span achieved for irradiated glioma bearing rats was similar to the one obtained with other radiotherapy techniques. This experimental tumor therapy study shows the feasibility of using X-ray minibeams with high doses in brain tumor radiotherapy.

Risk of Developing Cardiovascular Disease after Involved Node Radiotherapy versus Mantle Field for Hodgkin Lymphoma - Corrected Proof

2012-01-23

Purpose: Hodgkin lymphoma (HL) survivors are known to have increased cardiac mortality and morbidity. The risk of developing cardiovascular disease after involved node radiotherapy (INRT) is currently unresolved, inasmuch as present clinical data are derived from patients treated with the outdated mantle field (MF) technique.Methods and Materials: We included all adolescents and young adults with supradiaphragmatic, clinical Stage I–II HL treated at our institution from 2006 to 2010 (29 patients). All patients were treated with chemotherapy and INRT to 30 to 36 Gy. We then simulated a MF plan for each patient with a prescribed dose of 36 Gy. A logistic dose–response curve for the 25-year absolute excess risk of cardiovascular disease was derived and applied to each patient using the individual dose–volume histograms.Results: The mean doses to the heart, four heart valves, and coronary arteries were significantly lower for INRT than for MF treatment. However, the range in doses with INRT treatment was substantial, and for a subgroup of patients, with lymphoma below the fourth thoracic vertebrae, we estimated a 25-year absolute excess risk of any cardiac event of as much as 5.1%.Conclusions: Our study demonstrates a potential for individualizing treatment by selecting the patients for whom INRT provides sufficient cardiac protection for current technology; and a subgroup of patients, who still receive high cardiac doses, who would benefit from more advanced radiation technique.

po2 Fluctuation Pattern and Cycling Hypoxia in Human Cervical Carcinoma and Melanoma Xenografts - Corrected Proof

2012-01-23

Purpose: Blood perfusion in tumors is spatially and temporally heterogeneous, resulting in local fluctuations in tissue oxygen tension (po2) and tissue regions showing cycling hypoxia. In this study, we investigated whether the po2 fluctuation pattern and the extent of cycling hypoxia differ between tumor types showing high (e.g., cervical carcinoma xenograft) and low (e.g., melanoma xenograft) fractions of connective tissue-associated blood vessels.Methods and Materials: Two cervical carcinoma lines (CK-160 and TS-415) and two melanoma lines (A-07 and R-18) transplanted into BALB/c nu/nu mice were included in the study. Tissue po2 was measured simultaneously in two positions in each tumor by using a two-channel OxyLite fiber-optic oxygen-sensing device. The extent of acute and chronic hypoxia was assessed by combining a radiobiological and a pimonidazole-based immunohistochemical assay of tumor hypoxia.Results: The proportion of tumor regions showing po2 fluctuations, the po2 fluctuation frequency in these regions, and the relative amplitude of the po2 fluctuations were significantly higher in the melanoma xenografts than in the cervical carcinoma xenografts. Cervical carcinoma and melanoma xenografts did not differ significantly in the fraction of acutely hypoxic cells or the fraction of chronically hypoxic cells. However, the ratio between fraction of acutely hypoxic cells and fraction of chronically hypoxic cells was significantly higher in melanoma than in cervical carcinoma xenografts.Conclusions: Temporal heterogeneity in blood flow and tissue po2 in tumors may depend on tumor histology. Connective tissue surrounding microvessels may stabilize blood flow and po2 and, thus, protect tumor tissue from cycling hypoxia.

Postoperative Radiotherapy in Prostate Cancer: The Case of the Missing Target - Corrected Proof

2012-01-23

Purpose: Postoperative radiotherapy (XRT) increases survival in high-risk prostate cancer patients. Approximately 50% of patients on long-term follow-up relapse despite adjuvant XRT and the predominant site of failure remains local. Four consensus guidelines define postoperative clinical target volume (CTV) in prostate cancer. We explore the possibility that inadequate CTV coverage is an important cause of local failure. This study evaluates the utility of preoperative magnetic resonance imaging (MRI) in defining prostate bed CTV.Methods and Materials: Twenty prostate cancer patients treated with postoperative XRT who also had preoperative staging MRI were included. The four guidelines were applied and the CTVs were expanded to create planning target volumes (PTVs). Preoperative MRIs were fused with postoperative planning CT scans. MRI-based prostate and gross visible tumors were contoured. Three-dimensional (3D) conformal four- and six-field XRT plans were developed and dose–volume histograms analyzed. Subtraction analysis was conducted to assess the adequacy of prostate/gross tumor coverage.Results: Gross tumor was visible in 18 cases. In all 20 cases, the consensus CTVs did not fully cover the MRI-defined prostate. On average, 35% of the prostate volume and 32% of the gross tumor volume were missed using six-field 3D treatment plans. The entire MRI-defined gross tumor volume was completely covered in only two cases (six-field plans). The expanded PTVs did not cover the entire prostate bed in 50% of cases. Prostate base and mid-zones were the predominant site of inadequate coverage.Conclusions: Current postoperative CTV guidelines do not adequately cover the prostate bed and/or gross tumor based on preoperative MRI imaging. Additionally, expanded PTVs do not fully cover the prostate bed in 50% of cases. Inadequate CTV definition is likely a major contributing factor for the high risk of relapse despite adjuvant XRT. Preoperative imaging may lead to more accurate CTV definition, which should result in further improvements in survival for patients with high-risk prostate cancer.

Resected Pancreatic Neuroendocrine Tumors: Patterns of Failure and Disease-Related Outcomes With or Without Radiotherapy - Corrected Proof

2012-01-23

Purpose: Pancreatic neuroendocrine tumors (NET) are rare and have better disease-related outcomes compared with pancreatic adenocarcinoma. Surgical resection remains the standard of care, although many patients present with locally advanced or metastatic disease. Little is known regarding the use of radiotherapy in the prevention of local recurrence after resection. To better define the role of radiotherapy, we performed an analysis of resected patients at our institution.Methods: Between 1994 and 2009, 33 patients with NET of the pancreatic head and neck underwent treatment with curative intent at Duke University Medical Center. Sixteen patients were treated with surgical resection alone while an additional 17 underwent resection with adjuvant or neoadjuvant radiation therapy, usually with concurrent fluoropyrimidine-based chemotherapy (CMT). Median radiation dose was 50.4 Gy and median follow-up 28 months.Results: Thirteen patients (39%) experienced treatment failure. Eleven of the initial failures were distant, one was local only and one was local and distant. Two-year overall survival was 77% for all patients. Two-year local control for all patients was 87%: 85% for the CMT group and 90% for the surgery alone group (p = 0.38). Two-year distant metastasis-free survival was 56% for all patients: 46% and 69% for the CMT and surgery patients, respectively (p = 0.10).Conclusions: The primary mode of failure is distant which often results in mortality, with local failure occurring much less commonly. The role of radiotherapy in the adjuvant management of NET remains unclear.

Effect of Statins and Anticoagulants on Prostate Cancer Aggressiveness - Corrected Proof

2012-01-23

Purpose: Statins and anticoagulants (ACs) have both been associated with a less-aggressive prostate cancer (PCa) and a better outcome after treatment of localized PCa. The results of these studies might have been confounded because patients might often take both medications. We examined their respective influence on PCa aggressiveness at initial diagnosis.Materials and Methods: We analyzed 381 patients treated with either external beam radiotherapy or brachytherapy for low-risk (n = 152), intermediate-risk (n = 142), or high-risk (n = 87) localized PCa. Univariate and multivariate logistic regression analyses were used to investigate an association between these drug classes and prostate cancer aggressiveness. We tested whether the concomitant use of statins and ACs had a different effect than that of either AC or statin use alone.Results: Of the 381 patients, 172 (45.1%) were taking statins and 141 (37.0%) ACs; 105 patients (27.6%) used both. On univariate analysis, the statin and AC users were associated with the prostate-specific antigen (PSA) level (p = .017) and National Comprehensive Cancer Network risk group (p = .0022). On multivariate analysis, statin use was associated with a PSA level <10 ng/mL (odds ratio, 2.9; 95% confidence interval, 1.3–6.8; p = .012) and a PSA level >20 ng/mL (odds ratio, 0.29; 95% confidence interval, 0.08–0.83; p = .03). The use of ACs was associated with a PSA level >20 ng/mL (odds ratio, 0.13; 95% confidence interval, 0.02–0.59, p = .02).Conclusion: Both AC and statins have an effect on PCa aggressiveness, with statins having a more stringent relationship with the PSA level, highlighting the importance of considering statin use in studies of PCa aggressiveness.

Correlation Between Radiation Dose to 18F-FDG-PET Defined Active Bone Marrow Subregions and Acute Hematologic Toxicity in Cervical Cancer Patients Treated with Chemoradiotherapy - Corrected Proof

2012-01-23

Purpose: To test the hypothesis that radiation dose to 18F-fluorodeoxyglucose positron emission tomography (18F-FDG-PET)-defined active bone marrow (BMACT) subregions is correlated with hematologic toxicity in cervical cancer patients treated with chemoradiotherapy.Methods and Materials: The conditions of 26 women with cervical cancer who underwent 18F-FDG-PET before treatment with concurrent cisplatin and intensity-modulated radiation therapy were analyzed. BMACT was defined as the subregion of total bone marrow (BMTOT) with a standardized uptake value (SUV) equal to or above the mean for that individual. Inactive bone marrow (BMINACT) was defined as BMTOT − BMACT. Generalized linear modeling was used to test the correlation between BMACT and BMINACT dose–volume metrics and hematologic nadirs, particularly white blood cell count (WBC) and absolute neutrophil count (ANC).Results: Increased BMACT mean dose was significantly associated with decreased log(WBC) nadir (β = −0.04; 95% CI, −0.07to −0.01; p = 0.009), decreased log(ANC) nadir (β = −0.05; 95% CI, −0.08 to −0.02; p = 0.006), decreased hemoglobin nadir (β = −0.16; 95% CI, −0.27 to −0.05; p = 0.010), and decreased platelet nadir (β = −6.16; 95% CI, −9.37 to −2.96; p < 0.001). By contrast, there was no association between BMINACT mean dose and log(WBC) nadir (β = −0.01; 95% CI, −0.06 to 0.05; p = 0.84), log(ANC) nadir (β = −0.03; 95% CI, −0.10 to 0.04; p = 0.40), hemoglobin nadir (β = −0.09; 95% CI, −0.31 to 0.14; p = 0.452), or platelet nadir (β = −3.47; 95% CI, −10.44 to 3.50; p = 0.339).Conclusions: Irradiation of BM subregions with higher 18F-FDG-PET activity was associated with hematologic toxicity, supporting the hypothesis that reducing dose to BMACT subregions could mitigate hematologic toxicity. Future investigation should seek to confirm these findings and to identify optimal SUV thresholds to define BMACT.

The Impact of Brachytherapy on Prostate Cancer–Specific Mortality for Definitive Radiation Therapy of High-Grade Prostate Cancer: A Population-Based Analysis - Corrected Proof

2012-01-23

Purpose: This population-based analysis compared prostate cancer–specific mortality (PCSM) in a cohort of patients with high-risk prostate cancer after nonsurgical treatment with external beam radiation therapy (EBRT), brachytherapy (BT), or combination (BT + EBRT).Methods and Materials: We identified from the Surveillance, Epidemiology and End Results database patients diagnosed from 1988 through 2002 with T1–T3N0M0 prostate adenocarcinoma of poorly differentiated grade and treated with BT, EBRT, or BT + EBRT. During this time frame, the database defined high grade as prostate cancers with Gleason score 8–10, or Gleason grade 4–5 if the score was not recorded. This corresponds to a cohort primarily with high-risk prostate cancer, although some cases where only Gleason grade was recorded may have included intermediate-risk cancer. We used multivariate models to examine patient and tumor characteristics associated with the likelihood of treatment with each radiation modality and the effect of radiation modality on PCSM.Results: There were 12,745 patients treated with EBRT (73.5%), BT (7.1%), or BT + EBRT (19.4%) included in the analysis. The median follow-up time for all patients was 6.4 years. The use of BT or BT + EBRT increased from 5.1% in 1988–1992 to 31.4% in 1998–2002. Significant predictors of use of BT or BT + EBRT were younger age, later year of diagnosis, urban residence, and earlier T-stage. On multivariate analysis, treatment with either BT (hazard ratio, 0.66; 95% confidence interval, 0.49–0.86) or BT + EBRT (hazard ratio, 0.77; 95% confidence ratio, 0.66–0.90) was associated with significant reduction in PCSM compared with EBRT alone.Conclusion: In patients with high-grade prostate cancer, treatment with brachytherapy is associated with reduced PCSM compared with EBRT alone. Our results suggest that brachytherapy should be investigated as a component of definitive treatment strategies for patients with high-risk prostate cancer.

Individualized Nonadaptive and Online-Adaptive Intensity-Modulated Radiotherapy Treatment Strategies for Cervical Cancer Patients Based on Pretreatment Acquired Variable Bladder Filling Computed Tomography Scans - Corrected Proof

2012-01-23

Purpose: To design and evaluate individualized nonadaptive and online-adaptive strategies based on a pretreatment established motion model for the highly deformable target volume in cervical cancer patients.Methods and Materials: For 14 patients, nine to ten variable bladder filling computed tomography (CT) scans were acquired at pretreatment and after 40 Gy. Individualized model-based internal target volumes (mbITVs) accounting for the cervix and uterus motion due to bladder volume changes were generated by using a motion-model constructed from two pretreatment CT scans (full and empty bladder). Two individualized strategies were designed: a nonadaptive strategy, using an mbITV accounting for the full-range of bladder volume changes throughout the treatment; and an online-adaptive strategy, using mbITVs of bladder volume subranges to construct a library of plans. The latter adapts the treatment online by selecting the plan-of-the-day from the library based on the measured bladder volume. The individualized strategies were evaluated by the seven to eight CT scans not used for mbITVs construction, and compared with a population-based approach. Geometric uniform margins around planning cervix–uterus and mbITVs were determined to ensure adequate coverage. For each strategy, the percentage of the cervix–uterus, bladder, and rectum volumes inside the planning target volume (PTV), and the clinical target volume (CTV)-to-PTV volume (volume difference between PTV and CTV) were calculated.Results: The margin for the population-based approach was 38 mm and for the individualized strategies was 7 to 10 mm. Compared with the population-based approach, the individualized nonadaptive strategy decreased the CTV-to-PTV volume by 48% ± 6% and the percentage of bladder and rectum inside the PTV by 5% to 45% and 26% to 74% (p < 0.001), respectively. Replacing the individualized nonadaptive strategy by an online-adaptive, two-plan library further decreased the percentage of bladder and rectum inside the PTV (0% to 10% and −1% to 9%; p < 0.004) and the CTV-to-PTV volume (4–96 ml).Conclusions: Compared with population-based margins, an individualized PTV results in better organ-at-risk sparing. Online-adaptive radiotherapy further improves organ-at-risk sparing.

Prostate Brachytherapy with Oblique Needles to Treat Large Glands and Overcome Pubic Arch Interference - Corrected Proof

2012-01-23

Purpose: First, to show that low-dose-rate prostate brachytherapy plans using oblique needle trajectories are more successful than parallel trajectories for large prostates with pubic arch interference (PAI); second, to test the accuracy of delivering an oblique plan by using a three-dimensional (3D) transrectal ultrasonography (TRUS)-guided mechatronic system.Methods and Materials: Prostates were contoured for 5 subjects’ 3D TRUS images showing a maximum PAI of ≤1 cm and a prostate volume of <50 cc. Two planning studies were done. First, prostate contours were artificially enlarged to 45 to 80 cc in 5- to 10-cc increments for a single subject. Second, all subject prostate contours were enlarged to 60 cc. For each study, three types of plans were manually created for comparison: a parallel needle template (PT) plan, a parallel needle no-template (PNT) plan, and an oblique needle no-template (OBL) plan. Needle positions and angles were not discretized for nontemplate plans. European Society for Therapeutic Radiology and Oncology dose-volume histogram guidelines, iodine-125 (145-Gy prescription, 0.43 U), and needle angles of <15° were used. An OBL plan was delivered to a pubic arch containing a 60-cc prostate phantom that mimicked the anatomy of the subject with the greatest PAI (23% by volume).Results: In the increasing-prostate volume study, OBL plans were successful for prostates of ≤80 cc, and PT plans were successful for prostates of <65 cc. In paired, one-sided t tests for the 60-cc volume study, OBL plans showed dosimetric improvements for all organs compared to both of the parallel type plans (p < 0.05); PNT plans showed a benefit only in planning target volumes receiving more than 100 Gy compared to PT plans. A computed tomography scan of the phantom showed submillimeter seed placement accuracy in all directions.Conclusion: OBL plans were significantly better than parallel plans, and an OBL plan was accurately delivered to a 60-cc prostate phantom with 23% PAI by volume.

Patterns of Radiotherapy Practice for Patients with Cervical Cancer in Japan, 2003–2005: Changing Trends in the Pattern of Care Process - Corrected Proof

2012-01-23

Purpose: The patterns of care study (PCS) of radiotherapy for cervical cancer in Japan over the last 10 years was reviewed.Methods and Materials: The Japanese PCS working group analyzed data from 1,200 patients (1995–1997, 591 patients; 1999–2001, 324 patients; 2003–2005, 285 patients) with cervical cancer treated with definitive radiotherapy in Japan.Results: Patients in the 2001–2003 survey were significantly younger than those in the 1999–2001 study (p < 0.0001). Histology, performance status, and International Federation of Gynecology and Obstetrics stage were not significantly different among the three survey periods. Use of combinations of chemotherapy has increased significantly during those periods (1995–1997, 24%; 1999–2001, 33%; 2003–2005, 54%; p < 0.0001). The ratio of patients receiving concurrent chemotherapy has also dramatically increased (1995–1997, 20%; 1999–2001, 54%; 2003–2005, 83%; p < 0.0001). As for external beam radiotherapy (EBRT), the application rate of four-field portals has greatly increased over the three survey periods (1995–1997, 2%; 1999–2001, 7%; 2003–2005, 21%; p < 0.0001). In addition, the use of an appropriate beam energy for EBRT has shown an increase (1995–1997, 67%; 1999–2001, 74%; 2003–2005, 81%; p = 0.064). As for intracavitary brachytherapy (ICBT), an iridium source has become increasingly popular (1995–1997, 27%; 1999–2001, 42%; 2003–2005, 84%; p < 0.0001). Among the three surveys, the ratio of patients receiving ICBT (1995–1997, 77%; 1999–2001, 82%; 2003–2005, 78%) has not changed. Although follow-up was inadequate in each survey, no significant survival differences were observed (p = 0.36), and rates of late Grade 3 or higher toxicity were significantly different (p = 0.016).Conclusions: The Japanese PCS has monitored consistent improvements over the past 10 years in the application of chemotherapy, timing of chemotherapy, and EBRT methods. However, there is still room for improvement, especially in the clinical practice of ICBT.