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Abstract: Purpose: Breast cancer is managed by a multidisciplinary team with a goal for the timely provision of high quality care. Given radiation oncologist (RO) time constraints, an opportunity arises for task delegation of breast seroma target delineation to an advanced practice clinical specialist radiation therapist (CSRT) with clinical and technical expertise to facilitate treatment planning. To explore this further, we quantitatively evaluated the variability in post-surgical seroma delineation between the CSRT and ROs. Methods: Specialized site specific training was provided to the CSRT, who, with 7 ROs, independently contoured the seroma and graded its clarity, using the cavity visualization score (CVS), for 20 patients with clinical stage Tis-2N0 breast tumors. The conformity indices were analyzed for all possible pairs of delineations. The estimated “true” seroma contour was derived from the RO contours using the simultaneous truth and performance level estimation algorithm. Generalized kappa coefficient and center of mass metrics were used to examine the performance level of the CSRT in seroma delineations. Results: The CVS of the CSRT correlated well with the mean RO-group CVS, (Spearman ρ = 0.87, P < .05). The mean seroma conformity index for the RO group was 0.61 and 0.65 for the CSRT; a strong correlation was observed between the RO and CSRT conformity indices (Spearman ρ = 0.95, P < .05). Almost perfect agreement levels were observed between the CSRT contours and the STAPLE RO consensus contours, with an overall kappa statistic of 0.81 (P < .0001). The average center of mass shift between the CSRT and RO consensus contour was 1.69 ± 1.13 mm. Conclusions: Following specialized education and training, the CSRT delineated seroma targets clinically comparable with those of the radiation oncologists in women with early breast tumors suitable for accelerated partial breast or whole breast radiotherapy following lumpectomy. This study provides support for potential task delegation of breast seroma delineation to the CSRT in our current multidisciplinary environment. Further study is needed to assess the impact of this role expansion on radiotherapy system efficiency. [Copyright &y& Elsevier]

Background and purpose This study describes the process and outcomes of breast radiotherapy (RT) quality assurance (QA) rounds, seeking to identify variables associated with plan modifications. Materials and methods Real-time data were prospectively collected over 2 years. Descriptive statistics determined the proportion of cases requiring no (A), minor (B), or major (C) modifications, which were then subjected to univariate and multivariate analyses. Results A total of 2223 breast cancer QA cases were reviewed; 47 cases (2.1%) underwent a minor, and 52 cases (2.3%) required a major modification. Common changes included boost, volume, seroma, and bolus. On univariate analysis, regional nodal irradiation (RNI), tumour size, and axillary node dissection were significantly associated with major modifications. Upon multivariate analysis, the only independent predictor was RNI (OR 2.12, p = 0.0075). For patients with no RNI, <2 cm tumours, no axillary lymph node dissection, and no boosts ( n = 420); the likelihood of category C was only 1.4%. Conclusions It is feasible to conduct QA review for all breast cancer cases prior to commencing RT. Patients undergoing RNI had a higher likelihood of plan modifications; a group with low risk of modification was identified, which could direct future re-structuring of QA rounds. [ABSTRACT FROM AUTHOR]

Purpose: To determine the feasibility and benefits of optimized magnetic resonance imaging (MRI)-guided brachytherapy (BT) for cancer of the cervix. Methods and Materials: A total of 20 patients with International Federation of Gynecology and Obstetrics Stage IB-IV cervical cancer had an MRI-compatible intrauterine BT applicator inserted after external beam radiotherapy. MRI scans were acquired, and the gross tumor volume at diagnosis and at BT, the high-risk (HR) and intermediate-risk clinical target volume (CTV), and rectal, sigmoid, and bladder walls were delineated. Pulsed-dose-rate BT was planned and delivered in a conventional manner. Optimized MRI-based plans were developed and compared with the conventional plans. Results: The HR CTV and intermediate-risk CTV were adequately treated (the percentage of volume treated to ≥100% of the intended dose was >95%) in 70% and 85% of the patients with the conventional plans, respectively, and in 75% and 95% of the patients with the optimized plans, respectively. The minimal dose to the contiguous 2 cm3 of the rectal, sigmoid, and bladder wall volume was 16 ± 6.2, 25 ± 8.7, and 31 ± 9.2 Gy, respectively. With MRI-guided BT optimization, it was possible to maintain coverage of the HR-CTV and reduce the dose to the normal tissues, especially in patients with small tumors at BT. In these patients, the HR percentage of volume treated to ≥100% of the intended dose approached 100% in all cases, and the minimal dose to the contiguous 2-cm3 of the rectum, sigmoid, and bladder was 12–32% less than with conventional BT planning. Conclusion: MRI-based BT for cervical cancer has the potential to optimize primary tumor dosimetry and reduce the dose to critical normal tissues, particularly in patients with small tumors. [Copyright &y& Elsevier]

Purpose: Internal tumor and organ movement is important when considering intensity-modulated radiotherapy for patients with cancer of the cervix because of the tight margins and steep dose gradients. In this study, the internal movement of the tumor, cervix, and uterus were examined using serial cinematic magnetic resonance imaging scans and point-of-interest analysis. Methods and Materials: Twenty patients with Stage IB-IVA cervical cancer underwent pelvic magnetic resonance imaging before treatment and then weekly during external beam radiotherapy. In each 30-min session, sequential T2-sagittal magnetic resonance imaging scans were obtained. The points of interest (cervical os, uterine canal, and uterine fundus) were traced on each image frame, allowing the craniocaudal and anteroposterior displacements to be measured. The mean displacements and trends were analyzed using mixed linear models. Prediction intervals were calculated to determine the internal target margins. Results: Large interscan motion was found for all three points of interest that was only partially explained by the variations in bladder and rectal filling. The intrascan motion was much smaller. Both inter- and intrascan motion was greatest at the fundus of the uterus, less along the canal, and least at the cervical os. The isotropic internal target margins required to encompass 90% of the interscan motion were 4 cm at the fundus and 1.5 cm at the os. In contrast, smaller margins of 1 cm and 0.45 cm, respectively, were adequate to encompass the intrascan motion alone. Conclusion: Daily soft-tissue imaging with correction for interfractional motion or adaptive replanning will be important if the benefits of intensity-modulated radiotherapy are to be maximized in women with cervical cancer. [Copyright &y& Elsevier]

Purpose: To measure regression of cancer of the uterine cervix during external beam radiotherapy using magnetic resonance imaging, derive radiobiologic parameters from a mathematical model of tumor regression, and compare these parameters with the pretreatment measurements of tumor hypoxia. Methods and Materials: A total of 27 eligible patients undergoing external beam radiotherapy for cervical cancer underwent weekly magnetic resonance imaging scans. The tumor volume was assessed on each of these scans and the rate of regression plotted. A radiobiologic model was formulated to simulate the effect on tumor regression of the surviving proportion of cells after 2 Gy (SP2 ), the cell clearance constant (clearance of irreparably damaged cells from the tumor [Tc ]), and accelerated repopulation. Nonlinear regression analysis was used to fit the radiobiologic model to the magnetic resonance imaging-derived tumor volumes and to derive the estimates of SP2 and Tc for each patient. These were compared to the pretreatment hypoxia measurements. Results: The initial tumor volume was 8–209 cm3. The relative reduction in volume during treatment was 0.02–0.79. The simulations using representative values of the independent biologic variables derived from published data showed SP2 and Tc to strongly influence the shape of the volume–response curves. Nonlinear regression analysis yielded a median SP2 of 0.71 and median Tc of 10 days. Tumors with a high SP2 >0.71 were significantly more hypoxic at diagnosis (p = 0.02). Conclusion: The results of our study have shown that cervical cancer regresses during external beam radiotherapy, although marked variability is present among patients and is influenced by underlying biologic processes, including cellular sensitivity to radiotherapy and proliferation. Better understanding of the biologic mechanisms might facilitate novel adaptive treatment strategies in future studies. [Copyright &y& Elsevier]

Purpose: To evaluate the toxicity and effectiveness of celecoxib in combination with definitive chemoradiotherapy (CRT) in women with locally advanced cervical cancer. Methods and Materials: Thirty-one patients were accrued to a phase I–II trial of celecoxib 400 mg by mouth twice per day for 2 weeks before and during CRT. Tumor oxygenation (HP5) and interstitial fluid pressure (IFP) were measured before and 2 weeks after celecoxib administration alone. The median follow-up time was 2.7 years (range, 1.1–4.4 years). Results: The most common acute G3/4 toxicities were hematologic (4/31, 12.9%) and gastrointestinal (5/31, 16.1%) largely attributed to chemotherapy. Late G3/4 toxicity was seen in 4 of 31 patients (13.7% actuarial risk at 2 yr), including fistulas in 3 patients (9.7%). Within the first year of follow-up, 25 of 31 patients (81%) achieved complete response (CR), of whom 20 remained in CR at last follow-up. After 2 weeks of celecoxib administration before CRT, the median IFP decreased slightly (median absolute, –4.6 mm Hg; p = 0.09; relative, –21%; p = 0.07), whereas HP5 did not change significantly (absolute increase, 3.6%; p = 0.51; median relative increase, 11%; p = 0.27). No significant associations were seen between changes in HP5 or IFP and response to treatment (p = 0.2, relative HP5 change and p = 0.14, relative IFP change). Conclusions: Celecoxib in combination with definitive CRT is associated with acceptable acute toxicity, but higher than expected late complications. Celecoxib is associated with a modest reduction in the angiogenic biomarker IFP, but this does not correspond with tumor response. [Copyright &y& Elsevier]

Abstract: Objectives: Hypoxia and high interstitial fluid pressure (IFP) have been shown to independently predict for nodal and distant metastases, as well as survival, in patients with cervix cancer. Using data from our prospective trial, we updated a cohort of patients treated with definitive radiation alone without chemotherapy, to assess the long-term prognostic impact of these microenvironmental features. Methods: Between April 1994 and January 1999, 107 eligible patients with cervix cancer were entered into a prospective study of tumor oxygenation and IFP prior to primary radiation therapy. Oxygenation data are presented as the hypoxic proportion, defined as the percentage of pO2 readings <5mmHg (abbreviated as HP5). Patients with HP5 values >50% were considered to have hypoxic tumors. IFP is presented in mmHg, divided into high and low IFP groups by the median value. Patients ranged in age from 23 to 78 years with a mean of 53 years. The maximum tumor size ranged from 2 to 10cm, with a median diameter of 5cm. FIGO stage was IB in 28 patients, IIA in 4, IIB in 42 and IIIB in 33 patients. Twenty-two patients (21%) had evidence of pelvic lymph node involvement on staging CT abdomen/pelvis or MR pelvis. HP5 ranged from 0% to 99% with a median of 48%. IFP ranged from −3 to 48mmHg (median 19mmHg). Median follow-up was 6.7 years (range 0.9–10.6). Results: Disease-free survival (DFS) at 5 years was 50%. Five year DFS was 42% for patients with hypoxic tumors (HP5 >50%), and 58% in patients with oxygenated tumors (HR 1.01 per %, p =0.05). DFS at 5 years was 42% for patients with interstitial hypertension (IFP >19mmHg), and 63% in patients with IFP ⩽19mmHg (HR 1.05 per mmHg, p =0.001). In a multivariate analysis only tumor size (HR 1.2, p =0.009) pelvic nodal metastases (HR 3.3, p =0.0004) and IFP (HR 1.06, p =0.0005) were predictive of DFS. Because an interaction between nodal status and oxygenation was observed (p =0.03), further analysis indicated a borderline significant impact of HP5 in addition to tumor size in node negative patients (HR 1.01, p =0.06). These results were similar when local or distant relapse was used as an endpoint. Conclusions: These results confirm our initial finding of the strong independent prognostic impact of IFP for relapse and survival in patients with cervix cancer. In contrast, the independent prognostic impact of HP5 is of borderline significance and is limited to patients without imaging evidence of nodal metastases. However, these findings do not diminish the biologic significance of hypoxia, or the role of hypoxia and IFP as biomarkers of treatment response and as therapeutic targets. [Copyright &y& Elsevier]

Purpose: To compare survival and severe late radiation toxicity between patients who received continuous low-dose-rate (LDR) brachytherapy (BT) and pulsed-dose-rate (PDR) BT for cervical cancer. Methods and Materials: A retrospective review of cervical cancer patients who underwent primary radiotherapy with or without concurrent cisplatin was performed. Late Grade 3 or worse toxicities were assessed using the National Cancer Institute Common Toxicity Criteria. The study endpoints were overall and disease-free survival and the probability of severe late toxicity. Results: A total of 109 patients (65.7%) received LDR BT and 57 (34.3%) received PDR BT. Seventy patients received concurrent chemotherapy with cisplatin. The 3-year overall survival and disease-free survival rate was 70% and 57% for the LDR group and 82% and 70% for the PDR group, respectively (p = 0.25 and p = 0.19). The 3-year probability rate for late Grade 3 or worse toxicity was 7.4% for LDR BT patients and 7.6% for PDR BT patients, respectively (p = 0.69) and 6.9% and 7.6%, respectively, for concurrent chemotherapy vs. none (p = 0.69). Conclusion: No difference was found in severe late toxicity, overall survival, or disease-free survival between the LDR and PDR groups. [Copyright &y& Elsevier]

Purpose: To assess the feasibility and morbidity of sequential cytoreductive surgery, carboplatin/paclitaxel chemotherapy, and consolidative abdominopelvic radiotherapy (APRT) in ovarian cancer. Methods and Materials: Between 1998 and 2000, 29 patients with optimally cytoreduced epithelial ovarian cancer were treated with carboplatin (135 mg/m2) and paclitaxel (area under the curve [AUC] of 6) followed by APRT in a prospective protocol. All patients were clinically, radiographically, and biochemically (CA-125) free of disease at the completion of chemotherapy. Abdominopelvic radiotherapy was delivered using 6 MV anterior-posterior photon fields to encompass the peritoneal cavity. Median follow-up was 4 years. Results: Two patients experienced Radiation Therapy Oncology Group Grade 3 gastrointestinal toxicity during APRT; 6 patients, Grade 3 or 4 neutropenia; and 3 patients, Grade 3 or 4 thrombocytopenia. Overall, 10 patients had Grade 3 or 4 acute toxicity. All of the acute side effects resolved after treatment was completed, and there were no serious consequences such as sepsis or hemorrhage. Abdominopelvic radiotherapy was abandoned prematurely in 3 patients. Late side effects were seen in 5 patients, including 1 small bowel obstruction, 2 symptomatic sacral insufficiency fractures, 1 case of severe dyspareunia, and 1 case of prolonged fatigue. All resolved with supportive management. The 4-year actuarial disease-free survival was 57%, and the overall survival was 92%. Eleven of 12 patients who relapsed received salvage chemotherapy, which was well tolerated. Conclusions: Abdominopelvic radiotherapy after optimal surgery and carboplatin/paclitaxel chemotherapy is associated with an acceptable risk of acute and late side effects and does not limit subsequent salvage chemotherapy. Consolidative APRT warrants further investigation as a means of improving the outcome of patients with ovarian cancer. [Copyright &y& Elsevier]

Purpose: Factors affecting outcome in patients with surgicopathologic Stage II endometrial cancer are poorly defined. The purpose of this study was to determine prognostic factors in a series of patients treated according to standardized protocols at a single institution.Methods and Materials: One hundred and seventy patients referred to Princess Margaret Hospital after hysterectomy between 1984 and 1995 were retrospectively reviewed. One hundred and twenty patients received postoperative external beam radiotherapy and brachytherapy, 18 received external beam radiotherapy alone, five received brachytherapy alone, and 27 had no radiotherapy.Results: With a median follow-up of 5.1 years, overall and disease-free survival (DFS) at 5 years was 77% and 68%, respectively, and 24% of patients had relapsed. Significant independent adverse factors for DFS included age >65 (p = 0.0001), FIGO Stage IIB (p = 0.02), and capillary-lymphatic space (CLS) involvement (p = 0.0007). Prognostic factors for relapse were age (p = 0.0008), histologic grade (p = 0.01), and CLS (p = 0.01). A prognostic model based on the number of adverse prognostic factors (0–3) revealed that the 5-year survival rates for the four groups were as follows: 0%–85%, 1%–77%, 2%–55%, and 3%–11%. Combining the groups with 0 or 1 adverse factors resulted in a three-group variable that was strongly related to DFS (p < 0.0001).Conclusions: Patient age, stage, and CLS were significant factors for DFS, and age, grade, and CLS predicted time to relapse in Stage II endometrial cancer. A prognostic model for DFS using these factors can provide clinically meaningful outcome predictions. [Copyright &y& Elsevier]