Single vs. multiple fraction non-inferiority trial of stereotactic ablative radiotherapy for the comprehensive treatment of oligo-metastases/progression: SIMPLIFY-SABR-COMET.

BACKGROUND: Radiotherapy delivery regimens can vary between a single fraction (SF) and multiple fractions (MF) given daily for up to several weeks depending on the location of the cancer or metastases. With limited evidence comparing fractionation regimens for oligometastases, there is support to explore toxicity levels to nearby organs at risk as a primary outcome while using SF and MF stereotactic ablative radiotherapy (SABR) as well as explore differences in patient-reported quality of life and experience. METHODS: This study will randomize 598 patients in a 1:1 ratio between the standard arm (MF SABR) and the experimental arm (SF SABR). This trial is designed as two randomized controlled trials within one patient population for resource efficiency. The primary objective of the first randomization is to determine if SF SABR is non-inferior to MF SABR, with respect to healthcare provider (HCP)-reported grade 3-5 adverse events (AEs) that are related to SABR. Primary endpoint is toxicity while secondary endpoints include lesional control rate (LCR), and progression-free survival (PFS). The second randomization (BC Cancer sites only) will allocate participants to either complete quality of life (QoL) questionnaires only; or QoL questionnaires and a symptom-specific survey with symptom-guided HCP intervention. The primary objective of the second randomization is to determine if radiation-related symptom questionnaire-guided HCP intervention results in improved reported QoL as measured by the EuroQoL-5-dimensions-5levels (EQ-5D-5L) instrument. The primary endpoint is patient-reported QoL and secondary endpoints include: persistence/resolution of symptom reporting, QoL, intervention cost effectiveness, resource utilization, and overall survival. DISCUSSION: This study will compare SF and MF SABR in the treatment of oligometastases and oligoprogression to determine if there is non-inferior toxicity for SF SABR in selected participants with 1-5 oligometastatic lesions. This study will also compare patient-reported QoL between participants who receive radiation-related symptom-guided HCP intervention and those who complete questionnaires alone. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT05784428. Date of Registration: 23 March 2023.

Upfront Versus Delayed Systemic Therapy in Patients With Oligometastatic Cancer Treated With SABR in the Phase 2 SABR-5 Trial.

PURPOSE: The optimal sequencing of local and systemic therapy for oligometastatic cancer has not been established. This study retrospectively compared progression-free survival (PFS), overall survival (OS), and SABR-related toxicity between upfront versus delay of systemic treatment until progression in patients in the SABR-5 trial. METHODS AND MATERIALS: The single-arm phase 2 SABR-5 trial accrued patients with up to 5 oligometastases across SABR-5 between November 2016 and July 2020. Patients received SABR to all lesions. Two cohorts were retrospectively identified: those receiving upfront systemic treatment along with SABR and those for whom systemic treatment was delayed until disease progression. Patients treated for oligoprogression were excluded. Propensity score analysis with overlap weighting balanced baseline characteristics of cohorts. Bootstrap sampling and Cox regression models estimated the association of delayed systemic treatment with PFS, OS, and grade ≥2 toxicity. RESULTS: A total of 319 patients with oligometastases underwent treatment on SABR-5, including 121 (38%) and 198 (62%) who received upfront and delayed systemic treatment, respectively. In the weighted sample, prostate cancer was the most common primary tumor histology (48%) followed by colorectal (18%), breast (13%), and lung (4%). Most patients (93%) were treated for 1 to 2 metastases. The median follow-up time was 34 months (IQR, 24-45). Delayed systemic treatment was associated with shorter PFS (hazard ratio [HR], 1.56; 95% CI, 1.15-2.13; P = .005) but similar OS (HR, 0.90; 95% CI, 0.51-1.59; P = .65) compared with upfront systemic treatment. Risk of grade 2 or higher SABR-related toxicity was reduced with delayed systemic treatment (odds ratio, 0.35; 95% CI, 0.15-0.70; P < .001). CONCLUSIONS: Delayed systemic treatment is associated with shorter PFS without reduction in OS and with reduced SABR-related toxicity and may be a favorable option for select patients seeking to avoid initial systemic treatment. Efforts should continue to accrue patients to histology-specific trials examining a delayed systemic treatment approach.

Should organs at risk (OARs) be prioritized over target volume coverage in stereotactic ablative radiotherapy (SABR) for oligometastases? a secondary analysis of the population-based phase II SABR-5 trial.

BACKGROUND AND PURPOSE: Stereotactic ablative radiotherapy (SABR) for oligometastases may improve survival, however concerns about safety remain. To mitigate risk of toxicity, target coverage was sacrificed to prioritize organs-at-risk (OARs) during SABR planning in the population-based SABR-5 trial. This study evaluated the effect of this practice on dosimetry, local recurrence (LR), and progression-free survival (PFS). METHODS: This single-arm phase II trial included patients with up to 5 oligometastases between November 2016 and July 2020. Theprotocol-specified planning objective was to cover 95 % of the planning target volume (PTV) with 100 % of the prescribed dose, however PTV coverage was reduced as needed to meet OAR constraints. This trade-off was measured using the coverage compromise index (CCI), computed as minimum dose received by the hottest 99 % of the PTV (D99) divided by the prescription dose. Under-coverage was defined as CCI < 0.90. The potential association between CCI and outcomes was evaluated. RESULTS: 549 lesions from 381 patients were assessed. Mean CCI was 0.88 (95 % confidence interval [CI], 0.86-0.89), and 196 (36 %) lesions were under-covered. The highest mean CCI (0.95; 95 %CI, 0.93-0.97) was in non-spine bone lesions (n = 116), while the lowest mean CCI (0.71; 95 % CI, 0.69-0.73) was in spine lesions (n = 104). On multivariable analysis, under-coverage did not predict for worse LR (HR 0.48, p = 0.37) or PFS (HR 1.24, p = 0.38). Largest lesion diameter, colorectal and 'other' (non-prostate, breast, or lung) primary predicted for worse LR. Largest lesion diameter, synchronous tumor treatment, short disease free interval, state of oligoprogression, initiation or change in systemic treatment, and a high PTV Dmax were significantly associated with PFS. CONCLUSION: PTV under-coverage was not associated with worse LR or PFS in this large, population-based phase II trial. Combined with low toxicity rates, this study supports the practice of prioritizing OAR constraints during oligometastatic SABR planning.

Treatment With Stereotactic Ablative Radiotherapy for Up to 5 Oligometastases in Patients With Cancer: Primary Toxic Effect Results of the Nonrandomized Phase 2 SABR-5 Clinical Trial.

Importance: After the publication of the landmark SABR-COMET trial, concerns arose regarding high-grade toxic effects of treatment with stereotactic ablative body radiotherapy (SABR) for oligometastases. Objective: To document toxic effects of treatment with SABR in a large cohort from a population-based, provincial cancer program. Design, Setting, and Participants: From November 2016 to July 2020, 381 patients across all 6 cancer centers in British Columbia were treated in this single-arm, phase 2 trial of treatment with SABR for patients with oligometastatic or oligoprogressive disease. During this period, patients were only eligible to receive treatment with SABR in these settings in trials within British Columbia; therefore, this analysis is population based, with resultant minimal selection bias compared with previously published SABR series. Interventions: Stereotactic ablative body radiotherapy to up to 5 metastases. Main Outcomes and Measures: Rate of grade 2, 3, 4, and 5 toxic effects associated with SABR. Findings: Among 381 participants (122 women [32%]), the mean (SD; range) age was 68 (11.1; 30-97) years, and the median (range) follow-up was 25 (1-54) months. The most common histological findings were prostate cancer (123 [32%]), colorectal cancer (63 [17%]), breast cancer (42 [11%]), and lung cancer (33 [9%]). The number of SABR-treated sites were 1 (263 [69%]), 2 (82 [22%]), and 3 or more (36 [10%]). The most common sites of SABR were lung (188 [34%]), nonspine bone (136 [25%]), spine (85 [16%]), lymph nodes (78 [14%]), liver (29 [5%]), and adrenal (15 [3%]). Rates of grade 2, 3, 4, and 5 toxic effects associated with SABR (based on the highest-grade toxic effect per patient) were 14.2%; (95% CI, 10.7%-17.7%), 4.2% (95% CI, 2.2%-6.2%), 0%, and 0.3% (95% CI, 0%-0.8%), respectively. The cumulative incidence of grade 2 or higher toxic effects associated with SABR at year 2 by Kaplan-Meier analysis was 8%, and for grade 3 or higher, 4%. Conclusions and Relevance: This single-arm, phase 2 clinical trial found that the incidence of grade 3 or higher SABR toxic effects in this population-based study was less than 5%. Furthermore, the rates of grade 2 or higher toxic effects (18.6%) were lower than previously published for SABR-COMET (29%). These results suggest that SABR treatment for oligometastases has acceptable rates of toxic effects and potentially support further enrollment in randomized phase 3 clinical trials. Trial Registration: ClinicalTrials.gov Identifier: NCT02933242.

Predictors of Early Polymetastatic Relapse After SABR for up to 5 Oligometastases: A Secondary Analysis of the Phase II SABR-5 Trial.

PURPOSE: A subset of patients with oligometastatic cancer experience early widespread cancer dissemination and do not benefit from metastasis-directed therapy such as SABR. This study aimed to identify factors associated with early polymetastatic relapse (PMR). METHODS AND MATERIALS: The SABR-5 trial was a single arm phase 2 study conducted at all 6 regional cancer centers across British Columbia (BC), Canada. SABR for oligometastases was only offered on trial. Patients with up to 5 oligometastatic lesions (total, progressing, or induced) received SABR to all lesions. Patients were 18 years of age or older, Eastern Cooperative Oncology Group 0 to 2 and life expectancy ≥6 months. This secondary analysis evaluated factors associated with early PMR, defined as disease recurrence within 6 months of SABR, which is not amenable to further local treatment. Univariable and multivariable analyses were performed using binary logistic regression. The Kaplan-Meier method and log-rank tests assessed PMR-free survival and differences between risk groups, respectively. RESULTS: Between November 2016 and July 2020, 381 patients underwent treatment on SABR-5. A total of 16% of patients experienced PMR. Worse performance status (Eastern Cooperative Oncology Group 1-2 vs 0; hazard ratio [HR] = 2.01, P = .018), nonprostate/breast histology (HR = 3.64, P <.001), and oligoprogression (HR = 3.84, P <.001) were independent predictors for early PMR. Risk groups were identified with median PMR-free survival ranging from 5 months to not yet reached at the time of analysis. Rates of 3-year overall survival were 0%, 53% (95% confidence interval [CI], 48-58), 77% (95% CI, 73-81), and 93% (95% CI, 90-96) in groups 1 to 4, respectively (P <.001). CONCLUSIONS: Four distinct risk groups for early PMR are identified, which differ significantly in PMR-free survival and overall survival. The group with all 3 risk factors had a median PMR-free survival of 5 months and may not benefit from local ablative therapy alone. This model should be externally validated with data from other prospective trials.

Stereotactic ablative radiotherapy for the comprehensive treatment of 1-3 Oligometastatic tumors (SABR-COMET-3): study protocol for a randomized phase III trial.

BACKGROUND: A recent randomized phase II trial evaluated stereotactic ablative radiotherapy (SABR) in a group of patients with a small burden of oligometastatic disease (mostly with 1-3 metastatic lesions), and found that SABR was associated with a significant improvement in progression-free survival and a trend to an overall survival benefit, supporting progression to phase III randomized trials. METHODS: Two hundred and ninety-seven patients will be randomized in a 1:2 ratio between the control arm (consisting of standard of care [SOC] palliative-intent treatments), and the SABR arm (consisting of SOC treatment + SABR to all sites of known disease). Randomization will be stratified by two factors: histology (prostate, breast, or renal vs. all others), and disease-free interval (defined as time from diagnosis of primary tumor until first detection of the metastases being treated on this trial; divided as ≤2 vs. > 2 years). The primary endpoint is overall survival, and secondary endpoints include progression-free survival, cost effectiveness, time to development of new metastatic lesions, quality of life (QoL), and toxicity. Translational endpoints include assessment of circulating tumor cells, cell-free DNA, and tumor tissue as prognostic and predictive markers, including assessment of immunological predictors of response and long-term survival. DISCUSSION: This study will provide an assessment of the impact of SABR on survival, QoL, and cost effectiveness to determine if long-term survival can be achieved for selected patients with 1-3 oligometastatic lesions. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03862911. Date of registration: March 5, 2019.

External beam accelerated partial breast irradiation versus whole breast irradiation after breast conserving surgery in women with ductal carcinoma in situ and node-negative breast cancer (RAPID): a randomised controlled trial.

BACKGROUND: Whole breast irradiation delivered once per day over 3-5 weeks after breast conserving surgery reduces local recurrence with good cosmetic results. Accelerated partial breast irradiation (APBI) delivered over 1 week to the tumour bed was developed to provide a more convenient treatment. In this trial, we investigated if external beam APBI was non-inferior to whole breast irradiation. METHODS: We did this multicentre, randomised, non-inferiority trial in 33 cancer centres in Canada, Australia and New Zealand. Women aged 40 years or older with ductal carcinoma in situ or node-negative breast cancer treated by breast conserving surgery were randomly assigned (1:1) to receive either external beam APBI (38·5 Gy in ten fractions delivered twice per day over 5-8 days) or whole breast irradiation (42·5 Gy in 16 fractions once per day over 21 days, or 50 Gy in 25 fractions once per day over 35 days). Patients and clinicans were not masked to treatment assignment. The primary outcome was ipsilateral breast tumour recurrence (IBTR), analysed by intention to treat. The trial was designed on the basis of an expected 5 year IBTR rate of 1·5% in the whole breast irradiation group with 85% power to exclude a 1·5% increase in the APBI group; non-inferiority was shown if the upper limit of the two-sided 90% CI for the IBTR hazard ratio (HR) was less than 2·02. This trial is registered with ClinicalTrials.gov, NCT00282035. FINDINGS: Between Feb 7, 2006, and July 15, 2011, we enrolled 2135 women. 1070 were randomly assigned to receive APBI and 1065 were assigned to receive whole breast irradiation. Six patients in the APBI group withdrew before treatment, four more did not receive radiotherapy, and 16 patients received whole breast irradiation. In the whole breast irradiation group, 16 patients withdrew, and two more did not receive radiotherapy. In the APBI group, a further 14 patients were lost to follow-up and nine patients withdrew during the follow-up period. In the whole breast irradiation group, 20 patients were lost to follow-up and 35 withdrew during follow-up. Median follow-up was 8·6 years (IQR 7·3-9·9). The 8-year cumulative rates of IBTR were 3·0% (95% CI 1·9-4·0) in the APBI group and 2·8% (1·8-3·9) in the whole breast irradiation group. The HR for APBI versus whole breast radiation was 1·27 (90% CI 0·84-1·91). Acute radiation toxicity (grade ≥2, within 3 months of radiotherapy start) occurred less frequently in patients treated with APBI (300 [28%] of 1070 patients) than whole breast irradiation (484 [45%] of 1065 patients, p<0·0001). Late radiation toxicity (grade ≥2, later than 3 months) was more common in patients treated with APBI (346 [32%] of 1070 patients) than whole breast irradiation (142 [13%] of 1065 patients; p<0·0001). Adverse cosmesis (defined as fair or poor) was more common in patients treated with APBI than in those treated by whole breast irradiation at 3 years (absolute difference, 11·3%, 95% CI 7·5-15·0), 5 years (16·5%, 12·5-20·4), and 7 years (17·7%, 12·9-22·3). INTERPRETATION: External beam APBI was non-inferior to whole breast irradiation in preventing IBTR. Although less acute toxicity was observed, the regimen used was associated with an increase in moderate late toxicity and adverse cosmesis, which might be related to the twice per day treatment. Other approaches, such as treatment once per day, might not adversely affect cosmesis and should be studied. FUNDING: Canadian Institutes for Health Research and Canadian Breast Cancer Research Alliance.

SUPR-3D: A randomized phase iii trial comparing simple unplanned palliative radiotherapy versus 3d conformal radiotherapy for patients with bone metastases: study protocol.

BACKGROUND: Bone metastases in the lower spine and pelvis are effectively palliated with radiotherapy (RT), though this can come with side effects such as radiation induced nausea and vomiting (RINV). We hypothesize that high rates of RINV occur in part because of the widespread use of inexpensive simple unplanned palliative radiotherapy (SUPR), over more complex and resource intensive 3D conformal RT, such as volumetric modulated arc therapy (VMAT). METHODS: This is a randomized, multi-centre phase III trial of SUPR versus VMAT. We will accrue 250 patients to assess the difference in patient-reported RINV. This study is powered to detect a difference in quality of life between patients treated with VMAT vs. SUPR. DISCUSSION: This trial will determine if VMAT reduces early toxicity compared to SUPR and may provide justification for this more resource-intensive and costly form of RT. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT03694015 . Date of registration: October 3, 2018.

Population-based phase II trial of stereotactic ablative radiotherapy (SABR) for up to 5 oligometastases: SABR-5.

BACKGROUND: Oligometastases refer to a state of disease where cancer has spread beyond the primary site, but is not yet widely metastatic, often defined as 1-3 or 1-5 metastases in number. Stereotactic ablative radiotherapy (SABR) is an emerging radiotherapy technique to treat oligometastases that require further prospective population-based toxicity estimates. METHODS: This is a non-randomized phase II trial where all participants will receive experimental SABR treatment to all sites of newly diagnosed or progressing oligometastatic disease. We will accrue 200 patients to assess toxicity associated with this experimental treatment. The study was powered to give a 95% confidence on the risk of late grade 4 toxicity, anticipating a < 5% rate of grade 4 toxicity. DISCUSSION: SABR treatment of oligometastases is occurring off-trial at a high rate, without sufficient evidence of its efficacy or toxicity. This trial will provide necessary toxicity data in a population-based cohort, using standardized doses and organ at risk constraints, while we await data on efficacy from randomized phase III trials. TRIAL REGISTRATION: Registered through clinicaltrials.gov NCT02933242 on October 14, 2016 prospectively before patient accrual.

Acute Inflammatory Response During Neoadjuvant Chemotherapy for Locally Advanced Breast Cancer: A Case Report.

We report on a 56-year-old Caucasian female, diagnosed with locally advanced, hormone-receptor-positive, and human epidermal growth factor receptor 2 (HER2)-positive cancer of the left breast. The patient received neoadjuvant chemotherapy with adriamycin/cyclophosphamide (AC) followed by docetaxel/trastuzumab. A partial clinical and radiographical response was documented after four cycles of AC. Approximately one week after the first cycle of docetaxel and trastuzumab, the patient presented with diffuse edema, erythema, and induration involving the entire left breast. The differential diagnoses included infection, inflammatory response/reaction to docetaxel, or cancer progression. After a multidisciplinary review, the decision was made to stop the docetaxel and deliver neoadjuvant radiation treatment concurrent with trastuzumab. Approximately four weeks after radiation therapy completion, the patient underwent a left total mastectomy and axillary dissection, with pathologic complete response (pCR) in the breast and axillary nodal disease. After surgery, systemic therapy was resumed with paclitaxel and trastuzumab, with a plan to start adjuvant endocrine therapy after completion of chemotherapy. We will discuss clinical considerations in the management of the unexpected findings of acute inflammatory response in the breast and nodal regions during neoadjuvant chemotherapy. Associations between intrinsic breast cancer subtype and pCR in locally advanced breast cancer will also be reviewed.

Incorporating three-dimensional ultrasound into permanent breast seed implant brachytherapy treatment planning.

PURPOSE: Planning permanent breast seed implant (PBSI) brachytherapy using CT alone may reduce treatment accuracy because of differences in seroma visualization compared with ultrasound (US). This study evaluates dosimetric effects of seroma delineation in PBSI and the potential impact of incorporating three-dimensional (3D) US into PBSI treatment planning. METHODS AND MATERIALS: Spatially coregistered CT and 3D US images from 10 patients were retrospectively analyzed to simulate the PBSI procedure. Seromas contoured on CT and US defined clinical target volumes, CTVCT and CTVUS, which were expanded to create planning target volumes (PTVs). PBSI plans were generated using PTVCT alone, and the resulting coverage to PTVUS was evaluated. To assess the potential impact of transferring to an US-guided procedure, the CT-based plans were centered on CTVUS. The volume encompassed by both PTVs was used to evaluate how 3D US can affect the planning procedure. RESULTS: Median (range) PTVCTV100 was 95.6% (93.3-97.3%), resulting in PTVUS coverage of 91.5% (80.5-97.9%). Centering plans on CTVUS decreased PTVCTV100 by a mean of 10 ± 8%, and increased PTVUSV100 by 5 ± 4%. The combined PTVs were a mean 9±6% larger than PTVCT. Acceptable dosimetry to the combined PTVs resulted in sufficient coverage to individual PTVs but with a mean 11 ± 24% increase to skin dose and 6 ± 8% increase in breast V200. CONCLUSIONS: Differences in seroma visualization have dosimetric effects in PBSI. CT-based plans can underdose US-defined volumes and may not adequately translate to an US-guided procedure. Implementing 3D US into planning can potentially compensate for differences in delineation.

Predictors of adverse cosmetic outcome in the RAPID trial: an exploratory analysis.

PURPOSE: To evaluate factors associated with adverse cosmesis outcome in breast cancer patients randomized to accelerated partial breast irradiation (APBI) using 3-dimensional conformal radiation therapy or whole-breast irradiation in the RAPID (Randomized Trial of Accelerated Partial Breast Irradiation) trial. METHODS AND MATERIALS: Subjects were trial participants with nurse-assessed global cosmetic scores at baseline and at 3 years. Adverse cosmesis was defined as a score of fair or poor. Cosmetic deterioration was defined as any adverse change in score from baseline to 3 years. The analysis is based on data from the previously reported interim analysis. Logistic regression models were used to assess the association of risk factors for these outcomes among all patients and those treated with APBI only. RESULTS: Clinicopathologic characteristics were similar between subjects randomized to APBI (n=569) or whole-breast irradiation (n=539). For all subjects, factors associated with adverse cosmesis at 3 years were older age, central/inner tumor location, breast infection, smoking, seroma volume, breast volume, and use of APBI; factors associated with cosmetic deterioration were smoking, seroma volume, and use of APBI (P<.05). For APBI subjects, tumor location, smoking, age, and seroma volume were associated with adverse cosmesis (P<.05), and smoking was associated with cosmetic deterioration (P=.02). An independent association between the V95/whole-breast volume ratio and adverse cosmesis (P=.28) or cosmetic deterioration (P=.07) was not detected. On further exploration a V95/whole-breast volume ratio <0.15 was associated with a lower risk of cosmetic deterioration (p=.04), but this accounted for only 11% of patients. CONCLUSION: In the RAPID trial, a number of patient tumor and treatment-related factors, including the use of APBI, were associated with adverse cosmesis and cosmetic deterioration. For patients treated with APBI alone, the high-dose treatment volume was not independently associated with an adverse cosmetic outcome, and a useful clinical threshold could not be identified.

The experience of people with lung cancer with a volunteer-based lay navigation intervention at an outpatient cancer center.

OBJECTIVE: To describe the experiences of patients with lung cancer with a volunteer-based lay navigation intervention. METHODS: Forty patients with newly diagnosed lung cancer enrolled in a three-step navigation intervention delivered by trained volunteer lay navigators (VLNs), beginning prior to their first oncologist's appointment and ending before the start of treatment. Methodological triangulation of data was used in a mixed method study design. Cases were categorized based on the predominant needs met by the VLN: emotional, practical/informational, family, and complex. Data were analyzed using framework analysis. RESULTS: The provision of emotional support, information, and referrals to other services by the VLN were of particular benefit to the patient and their families. Satisfaction with the program and its timing was high; it was considered an effective means for patients to share concerns and have their needs attended to before starting treatment. CONCLUSION: This study demonstrates capacity for lay volunteers to address the multifaceted needs of lung cancer patients during their transition from primary care in the diagnosis to treatment phase. PRACTICE IMPLICATIONS: Using volunteers as navigators offers an opportunity to meet patient needs with minimal resources, increase access to services for patients, and improve the sustainability of the program.

The impact of peer review of volume delineation in stereotactic body radiation therapy planning for primary lung cancer: a multicenter quality assurance study.

INTRODUCTION: Although the value of peer review is increasingly recognized, there is little research documenting its impact in the setting of stereotactic body radiation therapy (SBRT) for lung cancer. This study determines the dosimetric effect of peer review of tumor and normal tissue contouring in lung SBRT planning. METHODS: Forty anonymized lung SBRT plans were retrospectively evaluated post treatment. Each plan was independently reviewed by two to three radiation oncologists using established institutional guidelines. For each structure, reviewers recorded recommendations for "no change," "minor change," "major change," or "missing contour" and provided a modified or new contour as needed. Dose-volume histograms were analyzed for dosimetric violations. RESULTS: Among 472 contoured structures evaluated, recommendations from peer review were 107 major change (23%), 176 minor change (37%), 157 no change (33%), and 32 missing (7%). Common major changes involved the skin (n = 20), heart (n = 18), and proximal bronchial tree (n = 15). Dose constraints were not achieved for 25 new or recontoured structures (5%), of which 17 involved the planning target volume (PTV). Among cases with PTV violations, the mean prescription dose coverage to the modified PTVs was 90%, compared with the protocol standard of greater than or equal to 95% coverage. The remaining violations involved the ribs (n = 5), spinal canal (n = 2), and heart (n = 1). CONCLUSIONS: Peer review of structure contouring resulted in significant changes in lung SBRT plans. Recontouring of several plans revealed violations of dose limits, most often involving inadequate PTV coverage. Peer review, especially of target volume delineation, is warranted to improve consistency and quality in lung SBRT planning.

Deformable versus rigid registration of PET/CT images for radiation treatment planning of head and neck and lung cancer patients: a retrospective dosimetric comparison.

BACKGROUND: The purpose of this study is to evaluate the clinical impact of using deformable registration in tumor volume definition between separately acquired PET/CT and planning CT images. METHODS: Ten lung and 10 head and neck cancer patients were retrospectively selected. PET/CT images were registered with planning CT scans using commercially available software. Radiation oncologists defined two sets of gross tumor volumes based on either rigidly or deformably registered PET/CT images, and properties of these volumes were then compared. RESULTS: The average displacement between rigid and deformable gross tumor volumes was 1.8 mm (0.7 mm) with a standard deviation of 1.0 mm (0.6 mm) for the head and neck (lung) cancer subjects. The Dice similarity coefficients ranged from 0.76-0.92 and 0.76-0.97 for the head and neck and lung subjects, respectively, indicating conformity. All gross tumor volumes received at least 95% of the prescribed dose to 99% of their volume. Differences in the mean radiation dose delivered to the gross tumor volumes were at most 2%. Differences in the fraction of the tumor volumes receiving 100% of the radiation dose were at most 5%. CONCLUSIONS: The study revealed limitations in the commercial software used to perform deformable registration. Unless significant anatomical differences between PET/CT and planning CT images are present, deformable registration was shown to be of marginal value when delineating gross tumor volumes.

Investigation of variability in image acquisition and contouring during 3D ultrasound guidance for partial breast irradiation.

BACKGROUND: Three-dimensional ultrasound (3DUS) at simulation compared to 3DUS at treatment is an image guidance option for partial breast irradiation (PBI). This study assessed if user dependence in acquiring and contouring 3DUS (operator variability) contributed to variation in seroma shifts calculated for breast IGRT. METHODS: Eligible patients met breast criteria for current randomized PBI studies. 5 Operators participated in this study. For each patient, 3 operators were involved in scan acquisitions and 5 were involved in contouring. At CT simulation (CT1), a 3DUS (US1) was performed by a single radiation therapist (RT). 7 to 14 days after CT1 a second CT (CT2) and 3 sequential 3DUS scans (US2a,b,c) were acquired by each of 3 RTs. Seroma shifts, between US1 and US2 scans were calculated by comparing geometric centers of the seromas (centroids). Operator contouring variability was determined by comparing 5 RT's contours for a single image set. Scanning variability was assessed by comparing shifts between multiple scans acquired at the same time point (US1-US2a,b,c). Shifts in seromas contoured on CT (CT1-CT2) were compared to US data. RESULTS: From an initial 28 patients, 15 had CT visible seromas, met PBI dosimetric constraints, had complete US data, and were analyzed. Operator variability contributed more to the overall variability in seroma localization than the variability associated with multiple scan acquisitions (95% confidence mean uncertainty of 6.2 mm vs. 1.1 mm). The mean standard deviation in seroma shift was user dependent and ranged from 1.7 to 2.9 mm. Mean seroma shifts from simulation to treatment were comparable to CT. CONCLUSIONS: Variability in shifts due to different users acquiring and contouring 3DUS for PBI guidance were comparable to CT shifts. Substantial inter-observer effect needs to be considered during clinical implementation of 3DUS IGRT.

pN0(i+) breast cancer: treatment patterns, locoregional recurrence, and survival outcomes.

PURPOSE: To examine treatment patterns, recurrence, and survival outcomes in patients with pN0(i+) breast cancer. METHODS AND MATERIALS: Subjects were 5999 women with AJCC (6th edition) pT1-3, pN0-N1a, M0 breast cancer diagnosed between 2003 and 2006. Of these, 4342 (72%) had pN0, 96 (2%) had pN0(i+), 349 (6%) had pNmic (micrometastases>0.2 mm to ≤2 mm), and 1212 (20%) had pN1a (1-3 positive macroscopic nodes) disease. Treatment characteristics and 5-year Kaplan-Meier local recurrence, regional recurrence (RR), locoregional recurrence (LRR), and overall survival were compared between nodal subgroups. Multivariable analysis was performed using Cox regression modeling. A 1:3 case-match analysis examined outcomes in pN0(i+) cases compared with pN0 controls matched for similar tumor and treatment characteristics. RESULTS: Median follow-up was 4.8 years. Adjuvant systemic therapy use increased with nodal stage: 81%, 92%, 95%, and 94% in pN0, pN0(i+), pNmic, and pN1a disease, respectively (P<.001). Nodal radiation therapy (RT) use also increased with nodal stage: 1.7% in pN0, 27% in pN0(i+), 33% in pNmic, and 63% in pN1a cohorts (P<.001). Five-year Kaplan-Meier outcomes in pN0 versus pN0(i+) cases were as follows: local recurrence 1.7% versus 3.7% (P=.20), RR 0.5% versus 2.2% (P=.02), and LRR 2.1% versus 5.8% (P=.02). There were no RR events in 26 patients with pN0(i+) disease who received nodal RT and 2 RR events in 70 patients who did not receive nodal RT. On multivariable analysis, pN0(i+) was not associated with worse locoregional control or survival. On case-match analysis, LRR and overall survival were similar between pN0(i+) and matched pN0 counterparts. CONCLUSIONS: Nodal involvement with isolated tumor cells is not a significant prognostic factor for LRR or survival in this study's multivariable and case-match analyses. These data do not support the routine use of nodal RT in the setting of pN0(i+) disease. Prospective studies are needed to define optimal locoregional management for women with pN0(i+) breast cancer.

Interim cosmetic and toxicity results from RAPID: a randomized trial of accelerated partial breast irradiation using three-dimensional conformal external beam radiation therapy.

PURPOSE: To report interim cosmetic and toxicity results of a multicenter randomized trial comparing accelerated partial-breast irradiation (APBI) using three-dimensional conformal external beam radiation therapy (3D-CRT) with whole-breast irradiation (WBI). PATIENTS AND METHODS: Women age > 40 years with invasive or in situ breast cancer ≤ 3 cm were randomly assigned after breast-conserving surgery to 3D-CRT APBI (38.5 Gy in 10 fractions twice daily) or WBI (42.5 Gy in 16 or 50 Gy in 25 daily fractions ± boost irradiation). The primary outcome was ipsilateral breast tumor recurrence (IBTR). Secondary outcomes were cosmesis and toxicity. Adverse cosmesis was defined as a fair or poor global cosmetic score. After a planned interim cosmetic analysis, the data, safety, and monitoring committee recommended release of results. There have been too few IBTR events to trigger an efficacy analysis. RESULTS: Between 2006 and 2011, 2,135 women were randomly assigned to 3D-CRT APBI or WBI. Median follow-up was 36 months. Adverse cosmesis at 3 years was increased among those treated with APBI compared with WBI as assessed by trained nurses (29% v 17%; P < .001), by patients (26% v 18%; P = .0022), and by physicians reviewing digital photographs (35% v 17%; P < .001). Grade 3 toxicities were rare in both treatment arms (1.4% v 0%), but grade 1 and 2 toxicities were increased among those who received APBI compared with WBI (P < .001). CONCLUSION: 3D-CRT APBI increased rates of adverse cosmesis and late radiation toxicity compared with standard WBI. Clinicians and patients are cautioned against the use of 3D-CRT APBI outside the context of a controlled trial.

Successful treatment of non-Hodgkin lymphoma associated immune thrombocytopenia with involved field radiotherapy.

Immune thrombocytopenia complicates the course and impacts the outcome of non-Hodgkin lymphoma (NHL-ITP, non-Hodgkin lymphoma-immune thrombocytopenic purpura). The response to corticosteroids and/or intravenous immune globulins is usually short lasting, but NHL-ITP usually responds to anti-lymphoma chemotherapy. It is not clear if this success is due to the elimination of the lymphomatous tissue or to the immunosuppressor/immunomodulator effect of chemotherapy. Myelosuppressive anti-lymphoma chemotherapy carries the risk of severe thrombocytopenia that may not respond adequately to platelet transfusion support. We report on a patient with recurrent diffuse large B-cell lymphoma that coincided with immune thrombocytopenia. Both diseases completely responded to involved field radiation therapy. This supports the hypothesis that at least in some cases of NHL-ITP, the lymphomatous clone secretes the anti-platelet antibodies. This supports the therapeutic decision making for these patients.