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Background: In the management of DCIS clinicians and patients (pts) must choose between the various options for breast conservation treatment based on an assessment of local recurrence (LR) risk. Traditional clinicopathologic (CP) factors such as age, size, grade, margin width or comedo necrosis, provide an average LR risk derived from clinical trials and population studies. The Oncotype DX® 12-gene assay for DCIS gives individual 10-yr LR risk estimates and has now been validated in two studies in a total of 893 pts. We report the 2nd study assessing the impact of the DCIS Score result on XRT recommendations. In addition, surveys assessing pt and physician confidence will provide insight into the overall clinical utility of the DCIS Score result. Baseline characteristics including the pre-assay LR risk and XRT recommendation are described here; final results on change in XRT recommendation from pre- to post-assay and distribution of the score across the CP factors will be presented. Methods: 13 U.S. sites enrolled pts with DCIS from 3/2014-5/2015. Pts with LCIS but no DCIS, invasive BC, or planned mastectomy were excluded. Data were prospectively collected on CP factors, physician estimates of LR risk, DCIS score, and pre/post XRT recommendation. Each pt had a surgeon and radiation oncologist complete study surveys. Pt surveys were also administered pre/post assay for decision conflict and the STAIT anxiety survey. The LR risk estimates and XRT recommendations were analyzed for all physicians as well as by specialty. Descriptive statistics summarized study variables. 95% Clopper-Pearson Exact CIs were calculated for percent change in XRT recommendation. McNemar's test was used to determine if the proportion of pts had a significant change in XRT recommendation post assay. Paired t-tests were used to compare physician estimates of recurrence risk pre/post assay. Results: Of the 121 pts enrolled, median age was 61y (34-83) and 80.2% were postmenopausal. Median size was 8mm and 40% were < 5mm; 22.3% were grade 1, 51.2% grade 2, and 26.4% grade 3. Comedo necrosis was noted in 55.4% and 19% had multiple foci. Median margin width was 3mm and 47.1% had margins 1-3mm. ER and PR by IHC were positive in 88.4% and 75.2% of pts. Among the 242 MD risk assessments, mean 10-yr LR risk was 14.8% (range 4-50%) for any LR; 14.2% for surgeons and 15.3% for radiation oncologists. The pre-assay XRT recommendation was 70.2%; 68.6% for surgeons and 71.9% for radiation oncologists. Conclusions: The role of new molecular tools such as the DCIS Score assay that provide individual risk estimates for LR on treatment decisions is evolving. The DCIS pts enrolled in the study reveal inclusion of baseline features like higher nuclear grade (26%), comedo necrosis (55%) and margin width of 1-3mm (47%) that have historically been associated with XRT use. This represents a continued broadening of the assay use from the predominantly lower risk DCIS cohort in the 1st validation study (E5194). The impact on XRT decisions is critical to establishing the clinical utility of the assay. The decision impact analysis, differences in use of the assay among surgeons and radiation oncologists and the impact on overall confidence with the treatment decision will be presented. Citation Format: Manders JB, Kuerer HM, Smith BD, McCluskey C, Farrar WB, Frazier TG, Li L, Leonard CE, Carter DL, Chawla S, Medeiros LE, Guenther JM, Castellini LE, Buchholz DJ, Mamounas EP, Wapnir IL, Horst KC, Chagpar A, Evans SB, Riker AI, Vali FS, Solin LJ, Jablon L, Recht A, Sharma R, Lu R, Sing AP, Hwang ES, White J. The 12-gene DCIS score assay: Impact on radiation treatment (XRT) recommendations and clinical utility. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P5-17-03.

Purpose: To report on the initial clinical use of a commercially available system to deliver gated treatment using implanted fiducials, in-room kV X-rays, and an infrared camera tracking system. Methods and Materials: ExacTrac Adaptive Gating from BrainLab is a localization system using infrared cameras and X-rays. Gating signals are the patient’s breathing pattern obtained from infrared reflectors on the patient. kV X-rays of an implanted fiducial are synchronized to the breathing pattern. After localization and shift of the patient to isocenter, the breathing pattern is used to gate the radiation. Feasibility tests included localization accuracy, radiation output constancy, and dose distributions with gating. Clinical experience is reported on treatment of patients with small lung lesions. Results: Localization accuracy of a moving target with gating was 1.7 mm. Dose constancy measurements showed insignificant change in output with gating. Improvements of dose distributions on moving targets improved with gating. Eleven patients with lung lesions were implanted with 20 mm × 0.7 mm gold coil (Visicoil). The implanted fiducial was used to localize and treat the patients with gating. Treatment planning and repeat computed tomographic scans showed that the change in center of gross target volume (GTV) to implanted marker averaged 2.47 mm due in part to asymmetric tumor shrinkage. Conclusion: ExacTrac Adaptive Gating has been used to treat lung lesions. Initial system evaluation verified its accuracy and usability. Implanted fiducials are visible in X-rays and did not migrate.

Purpose: To evaluate two different techniques for whole-breast treatments delivered using the Hi-ART II tomotherapy device. Methods and Materials: Tomotherapy uses the standard rotational helical delivery. Topotherapy uses a stationary gantry while delivering intensity-modulated treatments. CT scans from 5 breast cancer patients were used. The prescription dose was 50.4 Gy. Results: On average, 99% of the target volume received 95% of prescribed dose with either technique. If treatment times are restricted to less than 9 min, the average percentage ipsilateral lung receiving ≥20 Gy was 22% for tomotherapy vs. 10% for topotherapy. The ipsilateral lung receiving ≥50.4 Gy was 4 cc for tomotherapy vs. 27 cc for topotherapy. The percentage of left ventricle receiving ≥30 Gy was 14% with tomotherapy vs. 4% for topotherapy. The average doses to the contralateral breast and lung were 0.6 and 0.8 Gy, respectively, for tomotherapy vs. 0.4 and 0.3 Gy for topotherapy. Conclusions: Tomotherapy provides improved target dose homogeneity and conformality over topotherapy. If delivery times are restricted, topotherapy reduces the amount of heart and ipsilateral lung volumes receiving low doses. For whole-breast treatments, topotherapy is an efficient technique that achieves adequate target uniformity while maintaining low doses to sensitive structures.

The purpose of this investigation was to determine the effect of cellular proliferation and cell cycle stage on the ability of postirradiation 5-fluorouracil (5-FU) to radiosensitize cultured human colon adenocarcinoma Clone A cells. Cell survival curves were generated for irradiated: (a) log- and plateau-phase Clone A cells; and (b) Clone A cells separated by centrifugal elutriation into the various phases of the cell cycle; with and without postirradiation treatment with 100 {mu}g/ml 5-FU. Postirradiation treatment with 5-FU sensitized proliferating cells to a greater degree than it sensitized cells growing in plateau phase. The {beta} component of cell kill in log-phase cells was increased by a factor of 1.5 with a sensitizer enhancement ratio of 1.21 at the 0.01 survival level. Plateau-phase cells showed less radiosensitization (sensitizer enhancement ratio of 1.13 at the 0.01 survival level); however, there was a mild increase in both {alpha} and {beta} kill in plateau-phase cells. Elutriated G{sub 1} cells were the most radiosensitive, independent of treatment with 5-FU. The phase of the cell cycle had little effect on the ability of fluorouracil to radiosensitize Clone A cells. Proliferating cells are more susceptible to radiosensitization with 5-FU than plateau-phase cells are, but this effect appears tomore » be independent of the phase of the cell cycle. 18 refs., 4 figs., 3 tabs.« less

Pancreatic cancer remains the fourth leading cause of cancer-related deaths in adults in this country. Its etiology is unknown, and there is currently no effective method of early diagnosis. Although this article wil focus on the proper management of patients with potentially resectable disease, such patients represent the minority of those diagnosed with pancreatic cancer. Therefore, at most medical centers, clinical and basic science research is proceeding in parallel: while attempting to optimize the length and quality of life of patients with localized pancreatic tunors, research is also focusing on developing improved strategies for early and effective systemic therapy. For patients with localized pancreatic cancer, data from our institution support the use of detailed preoperative imaging studied to allow accurate assessment of tumor resectability. Patients found to have locally advanced or metastatic disease do not undergo laparotomy; biliary decompression, when necessary, is performed utilizing endoscopic or laparoscopic techniques. Pancreaticoduodenectomy is performed on carefully selected patients as part of a protocol-based clinical research program emphasizing the importance of multimodality management for patients with potentially resectable adenocarcinoma of the pancreatic head. ©1995 Wiley-Liss, Inc.

Purpose To evaluate the impact of 3-dimensional (3D) surface imaging on daily patient setup for breast radiotherapy. Materials and Methods Fifty patients undergoing treatment for whole breast radiotherapy were setup daily using an AlignRT system (VisionRT, London, UK) for 3D surface-based alignment. Daily alignments were performed against a reference surface topogram and shifts from skin marks were recorded daily. This investigation evaluated the following: (1) the performance of the surface-based imaging system for daily breast alignment; (2) the absolute displacements between setup with skin marks and setup with the surface-based imaging system; and (3) the dosimetric effect of daily alignments with skin marks versus surface-based alignments. Results Displacements from 1258 treatment fractions were analyzed. Sixty percent of those fractions (749) were reviewed against MV portal imaging in order to assess the performance of the AlignRT system. Daily setup errors were given as absolute displacements, comparing setup marks against shifts determined using the surface-based imaging system. Averaged over all patients, the mean displacements were 4.1 ± 2.6 mm, 2.7 ± 1.4 mm, and 2.6 ± 1.2 mm in the anteroposterior (AP), superoinferior (S/I), and left-right (L/R) directions, respectively. Furthermore, the standard deviation of the random error (σ) was 3.2 mm, 2.2 mm, and 2.2 mm in the A/P, S/I, and L/R directions, respectively. Conclusions Daily alignment with 3D surface imaging was found to be valuable for reducing setup errors when comparing with patient alignment from skin marks. The result of the surface-based alignments specifically showed that alignment with skin marks was noticeably poor in the anteroposterior directions. The overall dosimetric effect of the interfractional variations was small, but these variations showed a potential for increased dose deposition to both the heart and lung tissues. Although these interfractional variations would not negatively affect the quality of patient care for whole breast radiotherapy, it may require an increase in PTV margin, especially in cases of partial breast irradiation.

BACKGROUND. It is hypothesized that oligometastatic disease represents a state of potentially curable, limited metastases. Stereotactic body radiation therapy (SBRT) is an option for patients who are not amenable to or do not want resection. METHODS. From 2001 to 2006, 121 patients with ≤5 detectable metastases were enrolled in 2 prospective studies that used curative-intent SBRT. Most patients were treated with 10 fractions of 5 Gray. Stereotactic radiosurgery was offered to patients with brain metastases. RESULTS. The 2-year overall survival (OS), progression-free survival (PFS), local control (LC), and distant control (DC) rates were 50%, 26%, 67%, and 34%, respectively; and the respective 4-year rates values were 28%, 20%, 60%, and 25%. A greater net tumor volume predicted significantly worse OS, PFS, LC, and DC. Patients with breast cancer fared significantly better with respect to OS, PFS, LC, and DC; and patients with adrenal metastases had significantly worse OS, PFS, and DC despite the small number of such patients enrolled. Neither the number of metastatic lesions nor the number of organs involved was a significant predictor of outcome. Among 45 patients who remained alive at the last follow-up, 29 patients had no evidence of disease, including 23 patients with ≥2 years of follow-up. CONCLUSIONS. Oligometastatic disease is a potentially curable state of distant cancer spread. In this hypothesis-generating analysis, patients with less volume burden of their metastatic disease and those with primary breast cancer fared better. SBRT delivered with curative intent in patients with limited metastases should be investigated further. The Southwest Oncology Group is developing a prospective protocol to treat women who have limited breast cancer metastases with SBRT. Cancer 2008. © 2007 American Cancer Society.

Purpose To determine the precision of megavoltage computed tomography (MVCT)-based alignment of the seroma cavity for patients undergoing partial breast irradiation; and to determine whether accelerated partial breast irradiation (APBI) plans can be generated for TomoTherapy deliveries that meet the National Surgical Adjuvant Breast and Bowel Project (NSABP) B-39/Radiation Therapy Oncology Group (RTOG) 0413 protocol guidelines for target coverage and normal tissue dose limitations. Methods and Materials We obtained 50 MVCT images from 10 patients. An interuser study was designed to assess the alignment precision. Using a standard helical and a fixed beam prototype (“topotherapy”) optimizer, two APBI plans for each patient were developed. Results The precision of the MVCT-based seroma cavity alignment was better than 2 mm if averaged over the patient population. Both treatment techniques could be used to generate acceptable APBI plans for patients that fulfilled the recommended NSABP B-39/RTOG-0413 selection criteria. For plans of comparable treatment time, the conformation of the prescription dose to the target was greater for helical deliveries, while the ipsilateral lung dose was significantly reduced for the topotherapy plans. Conclusions The inherent volumetric imaging capabilities of a TomoTherapy Hi-Art unit allow for alignment of patients undergoing partial breast irradiation that is determined from the visibility of the seroma cavity on the MVCT image. The precision of the MVCT-based alignment was better than 2 mm (± standard deviation) when averaged over the patient population. Using the NSABP B-39/RTOG-0413 guidelines, acceptable APBI treatment plans can be generated using helical- or topotherapy-based delivery techniques.

Purpose : In an effort to reduce relapse in the liver and improve survival in patients with potentially resectable adenocarcinoma of the pancreatic head, we combined whole-liver irradiation with our standard preoperative chemoradiation regimen. Methods and Materials : Eleven patients with biopsy-proven, potentially resectable adenocarcinoma of the pancreatic head were treated with 50.4 Gy of external beam irradiation to the pancreas (1.8 Gy/day, 5 days/week) and concurrent continuous infusion 5-fluorouracil (300 mg/m 2 per day). The liver was treated with 23.4 Gy on Days 8 through 21 (13 fractions ; 1.8 Gy/fraction). Patients, who upon restaging with radiography and computed tomography were considered to have resectable tumors, were subsequently taken to surgery. If, at surgery, tumors were resectable, pancreaticoduodenectomy was performed, and 10 Gy of intraoperative electron-beam radiation therapy was delivered to the bed of the resected pancreas. Results : All 11 patients completed chemoradiation. Two treatment-related deaths occurred following chemoradiation, prompting premature termination of the study. Of seven patients taken to surgery, four underwent resection. Seven patients have died of disease, five with liver metastases. Conclusions : Prophylactic hepatic chemoradiation, as given in this study, was associated with two treatment-related deaths and a higher than expected incidence of subsequent liver metastases. Our data do not support the use of this treatment program in patients with adenocarcinoma of the pancreas.

To evaluate preoperative infusional chemoradiation for patients with operable rectal cancer. Preoperative chemoradiation therapy using infusional 5-fluorouracil (5-FU), (300 mg/m{sup 2}/day) together with daily irradiation (45 Gy/25 fractions/5 weeks) was administered to 77 patients with clinically Stage T3 rectal cancer. Endoscopic ultrasound confirmed the digital rectal exam in 63 patients. Surgery was performed approximately 6 weeks after the completion of chemoradiation therapy and included 25 abdominoperineal resections and 52 anal-sphincter-preserving procedures. Posttreatment tumor stages were T1-2, N0 in 35%, T3, N0 in 25%, and T1-3, N1 in 11%; 29% had no evidence of tumor. Local tumor control after chemoradiation was seen in 96% (74 out of 77); 2 patients had recurrent disease at the anastomosis site and were treated successfully with abdominoperineal resection. Overall, pelvic control was obtained in 99% (76 out of 77). The survival after chemoradiation was higher in patients without node involvement than in those having node involvement (p = n.s.). More patients with pathologic complete responses or only microscopic foci survived than did patients who had gross residual tumor (p = 0.07). The actuarial survival rate was 83% at 3 years; the median follow-up was 27 months, with a range of 3 to 68 months. Acute,more » perioperative, and late complications were not more numerous or more severe with chemoradiation therapy than with traditional radiation therapy (XRT) alone. Excellent treatment response allowed two-thirds of the patients to have an anal-sphincter-sparing procedure. Gross residual disease in the resected specimen indicates a poor prognosis, and therapies specifically targeting these patients may improve survival further. 22 refs., 2 figs., 3 tabs.« less

Results: Primary cancer sites included: breast (32%), colorectal (26%), lung/head & neck/esophagus (18%), pancreas/biliary/hepatic (6%), sarcoma (6%) and others (12%). Metastatic sites included lung (41%), thoracic lymph nodes (18%), liver (45%), pelvic/ abdominal lymph nodes (3%), adrenal glands (2%), brain (5%) and bone (12%). The number of metastatic lesions at presentation in each patient were 1 (30%), 2 (26%), 3 (23%), 4 (10%) and 5 (11%). The number of involved organs were: 1 (78%), 2 (19%), 3 (3%). The net GTV (sum of GTVs from all treated lesions) ranged from 0.3–422 ml (median 28 ml). Further metastatic progression was considered distant failure. Local failure was defined as radiographic growth (.20%) or pathological recurrence. The 2-year overall survival (OS), progression free survival (PFS), local control (LC) and distant control (DC) were 50%, 29%, 69% and 36% respectively. 4-year values were: 27%, 18%, 51% and 24%. The median OS and PFS were 24 months and 11 months respectively. Only 3 patients died from local progression (2 liver, 1 brain). The net GTV was significant on univariate (UVA) and multivariate (MVA) analysis for OS, PFS, DC and LC. Among patients who experienced a local failure, the median initial net GTV was 36 ml and mean net GTV was 78 ml, versus 27 ml and 41 ml respectively for patients without a documented local failure (p = 0.006 on t-test). On UVA and MVA, breast cancer patients fared significantly better with respect to OS, PFS, DC and LC. Patients with adrenal metastases had significantly worse OS, PFS and DC, despite the small number of such patients enrolled. Neither the number of metastatic lesions, nor the number of organs involved were significant predictors of OS or PFS. There was a trend towards worse DC with more organs involved. Among the 45 patients alive at last follow-up, 28 have no evidence of disease, including 22 patients with .2 years of follow-up. Conclusions: Oligometastatic disease is a potentially curable state of distant cancer spread. In our studies, patients with less volume burden of metastatic disease, and those with primary breast cancer fared better. The number of lesions and number of involved organs are not significant prognostic variables for OS or PFS. SBRT delivered with curative intent in patients with limited metastases should be investigated further. Author Disclosure: M.T. Milano, None; A.W. Katz, None; A.G. Muhs, None; A. Philip, None; D.J. Buchholz, None; M.C. Schell, None; P. Okunieff, Grant support from BrainLab AG (Heimstetten, Germany), B. Research Grant.

Purpose: To determine the clinical feasibility of a gated treatmentdelivery system from BrainLab™. Method and Materials: The Exactrac from BrainLab™ is a localization system that uses both infrared cameras and x‐rays. In gated mode, target location is determined by implanted fiducials. Breathing patterns are determined by infrared reflectors attached to the patient's surface. The User selects an x‐ray trigger point and radiotherapy beam‐on window relative to the breathing cycle. Multiple trigger levels may be selected to simulate a fluoroscopic mode to measure organ motion. Prior to clinical use feasibility tests including localization accuracy, gating window accuracy, and beam‐on accuracy were performed. Patients with small lung lesions were selected for treatment and implanted with a 20 by 0.7 mm gold fiducial. Treatment planning CT scans were taken at expiration breath hold with internal and external fiducials present. Results:_Localization accuracy was within 3mm when using 20% of the breathing cycle for beam on. To date, five patients with lung lesions were treated.Treatment times were approximately twenty minutes (standard dose fractionations). Implanted fiducials were well localizable in all patients. Target motion was on the order of 5mm average. Repeat CT scans showed implants did not migrate. The primary limitations with the system were related to breathing signal due to placement of external fiducials. Conclusion: Gating treatment technique from Exactrac™ has been used to treatlung lesions. This initial evaluation of the system verified the accuracy of the localization system under Gated mode. Implanted fiducials are localizable in patients, and gating is possible. The benefit of this system is the potential to decrease treatment margins and improve targeting. Continued evaluation of this system would help to define patient specific dose margins and beam‐on windows for treatment.

Purpose: To determine feasibility of megavoltage computed tomography (MVCT) imaging for low dose rate (LDR) brachytherapy for cervical carcinoma.Method and Materials: A helical tomotherapy treatment unit (Tomotherapy HiArt ,Tomotherapy Inc., Madison, WI) using a nominal 3.5 MV x‐ray beam was used to image a dosimetry phantom containing standard, non‐CT compatible Fletcher‐Suit applicators and dummy Cs‐137 tube sources (3M Model 6500). The phantom contained several small steel BB markers which were used as dose points. The MVCT images were transferred to a commercially available treatment planning system (CMS XiO 4.2, Computerized Medical Systems, St. Louis, MO). Digitally reconstructed radiographs (DRRs) were generated from the MVCT data set, and doses(dose rates) were calculated at the phantom dose points using standard 2D, film‐based dosimetry methods. Doses were also calculated using a CT‐based, 3D dosimetry technique in which the brachytherapy source tips and ends were localized directly on MVCT images. Separate experiments were performed to verify the spatial accuracy of the MVCT image reconstruction in‐phantom. Results: In‐phantom localization accuracy was 0.6 ± 0.3 mm, slightly less than the size of an axial MVCT image pixel and less than half of the MVCT slice thickness. Point doses in‐phantom calculated by 2D and by 3D methods agreed within an average of 1.5%. The techniques developed for successful MVCT imaging in‐phantom can be used to calculate 3D dose distributions in a human patient undergoing a traditional (non‐CT compatible) Fletcher‐Suit implant. Conclusion: MVCT imaging allows CT‐based dosimetry planning without the use of special, “CT‐compatible” applicators.

Objective The aim of this study was to determine the impact of the results of the 12-gene DCIS Score assay on (i) radiotherapy recommendations for patients with pure ductal carcinoma in situ (DCIS) following breast-conserving surgery (BCS), and (ii) patient decisional conflict and state anxiety. Methods Thirteen sites across the US enrolled patients (March 2014–August 2015) with pure DCIS undergoing BCS. Prospectively collected data included clinicopathologic factors, physician estimates of local recurrence risk, DCIS Score results, and pre-/post-assay radiotherapy recommendations for each patient made by a surgeon and a radiation oncologist. Patients completed pre-/post-assay decisional conflict scale and state-trait anxiety inventory instruments. Results The analysis cohort included 127 patients: median age 60 years, 80 % postmenopausal, median size 8 mm (39 % ≤5 mm), 70 % grade 1/2, 88 % estrogen receptor-positive, 75 % progesterone receptor-positive, 54 % with comedo necrosis, and 18 % multifocal. Sixty-six percent of patients had low DCIS Score results, 20 % had intermediate DCIS Score results, and 14 % had high DCIS Score results; the median result was 21 (range 0–84). Pre-assay, surgeons and radiation oncologists recommended radiotherapy for 70.9 and 72.4 % of patients, respectively. Post-assay, 26.4 % of overall recommendations changed, including 30.7 and 22.0 % of recommendations by surgeons and radiation oncologists, respectively. Among patients with confirmed completed questionnaires (n = 32), decision conflict (p = 0.004) and state anxiety (p = 0.042) decreased significantly from pre- to post-assay. Conclusions Individualized risk estimates from the DCIS Score assay provide valuable information to physicians and patients. Post-assay, in response to DCIS Score results, surgeons changed treatment recommendations more often than radiation oncologists. Further investigation is needed to better understand how such treatment changes may affect clinical outcomes. Electronic supplementary material The online version of this article (doi:10.1245/s10434-016-5583-7) contains supplementary material, which is available to authorized users.