ACR Appropriateness Criteria® nonsurgical treatment for locally advanced non-small-cell lung cancer: good performance status/definitive intent.

Concurrent chemotherapy/radiotherapy has been considered the standard treatment for patients with a good performance status and inoperable stage III non-small-cell lung cancer (NSCLC). Three-dimensional chemoradiation therapy and intensity-modulated radiation therapy have been reported to reduce toxicity and allow a dose escalation to 70 Gy and beyond. However, the Radiation Therapy Oncology Group 0617 trial recently showed that dose escalation from 60 Gy to 74 Gy with concurrent chemotherapy in stage III NSCLC was associated with higher toxicity and worse survival. A "one size fits all" treatment approach may need to be changed and adapted to each patient's particular disease and unique biologic/anatomic features, as well as the most appropriate radiotherapy modalities for that patient. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed every 3 years by a multidisciplinary expert panel. The guideline development and review include an extensive analysis of current medical literature from peer-reviewed journals and the application, by the panel, of a well-established consensus methodology (modified Delphi technique) to rate the appropriateness of imaging and treatment procedures. In instances in which evidence is lacking or not definitive, expert opinion may be used as the basis for recommending imaging or treatment.

Factors associated with acute esophagitis during radiation therapy for lung cancer.

INTRODUCTION: Limiting acute esophagitis remains a clinical challenge during the treatment of locally advanced non-small cell lung cancer (NSCLC). METHODS: Demographic, dosimetric, and acute toxicity data were prospectively collected for patients undergoing definitive radiation therapy +/- chemotherapy for stage II-III NSCLC from 2012 to 2022 across a statewide consortium. Logistic regression models were used to characterize the risk of grade 2 + and 3 + esophagitis as a function of dosimetric and clinical covariates. Multivariate regression models were fitted to predict the 50 % risk of grade 2 esophagitis and 3 % risk of grade 3 esophagitis. RESULTS: Of 1760 patients, 84.2 % had stage III disease and 85.3 % received concurrent chemotherapy. 79.2 % of patients had an ECOG performance status ≤ 1. Overall rates of acute grade 2 + and 3 + esophagitis were 48.4 % and 2.2 %, respectively. On multivariate analyses, performance status, mean esophageal dose (MED) and minimum dose to the 2 cc of esophagus receiving the highest dose (D2cc) were significantly associated with grade 2 + and 3 + esophagitis. Concurrent chemotherapy was associated with grade 2 + but not grade 3 + esophagitis. For all patients, MED of 29 Gy and D2cc of 61 Gy corresponded to a 3 % risk of acute grade 3 + esophagitis. For patients receiving chemotherapy, MED of 22 Gy and D2cc of 50 Gy corresponded to a 50 % risk of acute grade 2 + esophagitis. CONCLUSIONS: Performance status, concurrent chemotherapy, MED and D2cc are associated with acute esophagitis during definitive treatment of NSCLC. Models that quantitatively account for these factors can be useful in individualizing radiation plans.

Predictors of Early Hospice or Death in Patients With Inoperable Lung Cancer Treated With Curative Intent.

INTRODUCTION: Treatment for inoperable stage II to III non-small cell lung cancer (NSCLC) involves chemo-radiotherapy (CRT). However, some patients transition to hospice or die early during their treatment course. We present a model to prognosticate early poor outcomes in NSCLC patients treated with curative-intent CRT. METHODS AND MATERIALS: Across a statewide consortium, data was prospectively collected on stage II to III NSCLC patients who received CRT between 2012 and 2019. Early poor outcomes included hospice enrollment or death within 3 months of completing CRT. Logistic regression models were used to assess predictors in prognostic models. LASSO regression with multiple imputation were used to build a final multivariate model, accounting for missing covariates. RESULTS: Of the 2267 included patients, 128 experienced early poor outcomes. Mean age was 71 years and 59% received concurrent chemotherapy. The best predictive model, created parsimoniously from statistically significant univariate predictors, included age, ECOG, planning target volume (PTV), mean heart dose, pretreatment lack of energy, and cough. The estimated area under the ROC curve for this multivariable model was 0.71, with a negative predictive value of 95%, specificity of 97%, positive predictive value of 23%, and sensitivity of 16% at a predicted risk threshold of 20%. CONCLUSIONS: This multivariate model identified a combination of clinical variables and patient reported factors that may identify individuals with inoperable NSCLC undergoing curative intent chemo-radiotherapy who are at higher risk for early poor outcomes.

Long-term impact of young age at diagnosis on treatment outcome and patterns of failure in patients with ductal carcinoma in situ treated with breast-conserving therapy.

We reviewed our institution's long-term experience treating patients diagnosed with ductal carcinoma in situ (DCIS) of the breast with breast-conserving therapy (BCT) to determine the impact of patient age on outcome over time. All DCIS cases receiving BCT between 1980 and 1993 were reviewed. Patient demographics (including age <45) and pathologic factors were analyzed for effect on outcomes including ipsilateral breast tumor recurrence (IBTR) and survival. BCT included limited surgery (excisional biopsy or lumpectomy) followed by radiotherapy to the whole breast (median whole-breast dose: 50 Gy, median tumor bed dose: 60.4 Gy). One hundred and forty-five cases were evaluated; the median follow-up was 19.3 years. Twenty-five patients developed an IBTR, for 5-, 10-, 15-, and 20-year actuarial rates of 9.9%, 12.2%, 13.7%, and 17.5%, respectively. The 10-year ipsilateral rate of recurrence was 23.3% (<45 years) versus 9.1% (≥ 45 years) (p = 0.05). Younger patients more frequently developed invasive recurrences (20-year actuarial rates: 20.4% versus 12.8%, p = 0.22) and true recurrences/marginal misses of the index lesion (23.3% versus 9.7%, p = 0.04) with lower rates of contralateral breast cancer (0.0% and 0.0% versus 12.0% and 20.5%, p = < 0.01, at 10 and 20 years, respectively). Young women under the age of 45 diagnosed with DCIS have a greater risk of local recurrence with different patterns of failure following BCT, which is most notable within 10 years of diagnosis.

Cardiac and Pulmonary Dosimetric Parameters in Patients With Lung Cancer Undergoing Postoperative Radiation Therapy Across a Statewide Consortium.

PURPOSE: The recently published Lung Adjuvant Radiotherapy Trial (Lung ART) reported increased rates of cardiac and pulmonary toxic effects in the postoperative radiation therapy (PORT) arm. It remains unknown whether the dosimetric parameters reported in Lung ART are representative of contemporary real-world practice, which remains relevant for patients undergoing PORT for positive surgical margins. The purpose of this study was to examine heart and lung dose exposure in patients receiving PORT for non-small cell lung cancer across a statewide consortium. METHODS AND MATERIALS: From 2012 to 2022, demographic and dosimetric data were prospectively collected for 377 patients at 27 academic and community centers within the Michigan Radiation Oncology Quality Consortium undergoing PORT for nonmetastatic non-small cell lung cancer. Dosimetric parameters for target coverage and organ-at-risk exposure were calculated using data from dose-volume histograms, and rates of 3-dimensional conformal radiation therapy (3D-CRT) and intensity modulated radiation therapy (IMRT) utilization were assessed. RESULTS: Fifty-one percent of patients in this cohort had N2 disease at the time of surgery, and 25% had a positive margin. Sixty-six percent of patients were treated with IMRT compared with 32% with 3D-CRT. The planning target volume was significantly smaller in patients treated with 3D-CRT (149.2 vs 265.4 cm3; P < .0001). The median mean heart dose for all patients was 8.7 Gy (interquartile range [IQR], 3.5-15.3 Gy), the median heart volume receiving at least 5 Gy (V5) was 35.2% (IQR, 18.5%-60.2%), and the median heart volume receiving at least 35 Gy (V35) was 9% (IQR, 3.2%-17.7%). The median mean lung dose was 11.4 Gy (IQR, 8.1-14.3 Gy), and the median lung volume receiving at least 20 Gy (V20) was 19.6% (IQR, 12.7%-25.4%). These dosimetric parameters did not significantly differ by treatment modality (IMRT vs 3D-CRT) or in patients with positive versus negative surgical margins. CONCLUSIONS: With increased rates of IMRT use, cardiac and lung dosimetric parameters in this statewide consortium were slightly lower than those reported in Lung ART. These data provide useful benchmarks for treatment planning in patients undergoing PORT for positive surgical margins.

Prospective Evaluation of Limited-Stage Small Cell Lung Cancer Radiotherapy Fractionation Regimen Usage and Acute Toxicity in a Large Statewide Quality Collaborative.

PURPOSE: National guidelines on limited-stage small cell lung cancer (LS-SCLC) treatment give preference to a hyperfractionated regimen of 45 Gy in 30 fractions delivered twice daily; however, use of this regimen is uncommon compared with once-daily regimens. The purpose of this study was to characterize the LS-SCLC fractionation regimens used throughout a statewide collaborative, analyze patient and treatment factors associated with these regimens, and describe real-world acute toxicity profiles of once- and twice-daily radiation therapy (RT) regimens. METHODS AND MATERIALS: Demographic, clinical, and treatment data along with physician-assessed toxicity and patient-reported outcomes were prospectively collected by 29 institutions within the Michigan Radiation Oncology Quality Consortium between 2012 and 2021 for patients with LS-SCLC. We modeled the influence of RT fractionation and other patient-level variables clustered by treatment site on the odds of a treatment break specifically due to toxicity with multilevel logistic regression. National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0, incident grade 2 or worse toxicity was longitudinally compared between regimens. RESULTS: There were 78 patients (15.6% overall) treated with twice-daily RT and 421 patients treated with once-daily RT. Patients receiving twice-daily RT were more likely to be married or living with someone (65% vs 51%; P = .019) and to have no major comorbidities (24% vs 10%; P = .017). Once-daily RT fractionation toxicity peaked during RT, and twice-daily toxicity peaked within 1 month after RT. After stratifying by treatment site and adjusting for patient-level variables, once-daily treated patients had 4.11 (95% confidence interval, 1.31-12.87) higher odds of treatment break specifically due to toxicity than twice-daily treated patients. CONCLUSIONS: Hyperfractionation for LS-SCLC remains infrequently prescribed despite the lack of evidence demonstrating superior efficacy or lower toxicity of once-daily RT. With peak acute toxicity after RT and lower likelihood of a treatment break with twice-daily fractionation in real-word practice, providers may start using hyperfractionated RT more frequently.

Twenty-year outcomes after breast-conserving surgery and definitive radiotherapy for mammographically detected ductal carcinoma in situ.

BACKGROUND: Management of mammographically detected ductal carcinoma in situ (DCIS) at a single institution was reviewed to determine long-term clinical outcomes after treatment with breast-conserving therapy (BCT). METHODS: Data from all patient-cases with DCIS who received BCT between 1980 and 1993 were reviewed. Patient demographics and pathologic factors were analyzed for their effect on outcomes, including ipsilateral breast tumor recurrence (IBTR) and survival. BCT included breast-conserving surgery followed by external-beam radiotherapy to the whole breast, with 86 % of patients receiving a lumpectomy cavity boost. The median dose to the whole breast was 50 Gy and 60.4 Gy to the lumpectomy cavity. RESULTS: A total of 129 cases were evaluated; the median follow-up was 19.3 years. Twenty-one patients developed an ipsilateral breast tumor recurrence (IBTR), 76.2 % of which were invasive (n = 16). Fourteen recurrences (66 %) were within the same breast quadrant (true recurrence), while an additional 7 cases developed an IBTR elsewhere in the breast. True recurrences were more prevalent in women <45 years of age (20 %/24 % vs. 5.1 %/8 %) at 10 and 20 years (p = 0.02). The 5-, 10-, 15-, and 20-year actuarial rates of IBTR for this cohort were 8.7, 10.4, 12.1, and 16.3 % (IBTR), while overall survival at 5, 10, and 20 years was 97.6, 96.8, and 96.8 %, respectively. CONCLUSIONS: Mammographically detected DCIS remains a clinically distinct subset of noninvasive breast cancer. With 20 year follow-up, local control and overall survival are excellent after BCT.

Chemoradiation with Hypofractionated Proton Therapy in Stage II-III Non-Small Cell Lung Cancer: A Proton Collaborative Group Phase 2 Trial.

PURPOSE: Hypofractionated radiation therapy has been safely implemented in the treatment of early-stage non-small cell lung cancer (NSCLC) but not locally advanced NSCLC owing to prohibitive toxicities with photon therapy. Proton therapy, however, may allow for safe delivery of hypofractionated radiation therapy. We sought to determine whether hypofractionated proton therapy with concurrent chemotherapy improves overall survival. METHODS AND MATERIALS: The Proton Collaborative Group conducted a phase 1/2 single-arm nonrandomized prospective multicenter trial from 2013 through 2018. We received consent from 32 patients, of whom 28 were eligible for on-study treatment. Patients had stage II or III unresectable NSCLC (based on the 7th edition of the American Joint Committee on Cancer's staging manual) and received hypofractionated proton therapy at 2.5 to 4 Gy per fraction to a total 60 Gy with concurrent platin-based doublet chemotherapy. The primary outcome was 1-year overall survival comparable to the 62% reported for the Radiation Therapy Oncology Group (RTOG) 9410 trial. RESULTS: The trial closed early owing to slow accrual, in part, from a competing trial, RTOG 1308. Median patient age was 70 years (range, 50-86 years). Patients were predominantly male (n = 20), White (n = 23), and prior smokers (n = 27). Most had stage III NSCLC (n = 22), 50% of whom had adenocarcinoma. After a median follow-up of 31 months, the 1- and 3-year overall survival rates were 89% and 49%, respectively, and progression-free survival rates were 58% and 32%, respectively. No acute grade ≥3 esophagitis occurred. Only 14% developed a grade ≥3 radiation-related pulmonary toxic effect. CONCLUSIONS: Hypofractionated proton therapy delivered at 2.5 to 3.53 Gy per fraction to a total 60 Gy with concurrent chemotherapy provides promising survival, and additional examination through larger studies may be warranted.

Effect of Education and Standardization of Cardiac Dose Constraints on Heart Dose in Patients With Lung Cancer Receiving Definitive Radiation Therapy Across a Statewide Consortium.

PURPOSE: Cardiac radiation exposure is associated with an increased rate of adverse cardiac events in patients receiving radiation therapy for locally advanced non-small cell lung carcinoma (NSCLC). Previous analysis of practice patterns within the Michigan Radiation Oncology Quality Consortium (MROQC) revealed 1 in 4 patients received a mean heart dose >20 Gy and significant heterogeneity existed among treatment centers in using cardiac dose constraints. The purpose of this study is to analyze the effect of education and initiation of standardized cardiac dose constraints on heart dose across a statewide consortium. METHODS AND MATERIALS: From 2012 to 2020, 1681 patients from 27 academic and community centers who received radiation therapy for locally advanced NSCLC were included in this analysis. Dosimetric endpoints including mean heart dose (MHD), mean lung dose, and mean esophagus dose were calculated using data from dose-volume histograms. These dose metrics were grouped by year of treatment initiation for all patients. Education regarding data for cardiac dose constraints first occurred in small lung cancer working group meetings and then consortium-wide starting in 2016. In 2018, a quality metric requiring mean heart dose <20 Gy while maintaining dose coverage (D95) to the target was implemented. Dose metrics were compared before (2012-2016) versus after (2017-2020) initiation of interventions targeting cardiac constraints. Statistical analysis was performed using the Wilcoxon rank sum test. RESULTS: After education and implementation of the heart dose performance metric, mean MHD declined from an average of 12.2 Gy preintervention to 10.4 Gy postintervention (P < .0001), and the percentage of patients receiving MHD >20 Gy was reduced from 21.1% to 10.3% (P < .0001). Mean lung dose and mean esophagus dose did not increase, and target coverage remained unchanged. CONCLUSIONS: Education and implementation of a standardized cardiac dose quality measure across a statewide consortium was associated with a reduction of mean heart dose in patients receiving radiation therapy for locally advanced NSCLC. These dose reductions were achieved without sacrificing target coverage, increasing mean lung dose, or increasing mean esophagus dose. Analysis of the clinical ramifications of the reduction in cardiac doses is ongoing.

American Radium Society Appropriate Use Criteria for Radiation Therapy in Oligometastatic or Oligoprogressive Non-Small Cell Lung Cancer.

PURPOSE: Recent randomized studies have suggested improvements in progression-free and overall survival with the addition of stereotactic body radiation therapy (SBRT, also known as SABR) in patients with oligometastatic non-small cell lung cancer. Given the novelty and complexity of incorporating SBRT in the oligometastatic setting, the multidisciplinary American Radium Society Lung Cancer Panel was assigned to create appropriate use criteria on SBRT as part of consolidative local therapy for patients with oligometastatic and oligoprogressive non-small cell lung cancer. METHODS AND MATERIALS: A review of the current literature was conducted from January 1, 2008, to December 25, 2020, using the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines to systematically search the PubMed database to retrieve a comprehensive set of relevant articles. RESULTS: Based on representation in existing randomized trials, the panel defined the term "oligometastasis" as ≤3 metastatic deposits (not including the primary tumor) in the previously untreated setting or after first-line systemic therapy after the initial diagnosis. "Oligoprogression" also referred to ≤3 discrete areas of progression in the setting of prior or ongoing receipt of systemic therapy. In all appropriate patients, the panel strongly recommends enrollment in a clinical trial whenever available. For oligometastatic disease, administering first-line systemic therapy followed by consolidative radiation therapy (to all sites plus the primary/nodal disease) is preferred over up-front radiation therapy. Owing to a dearth of data, the panel recommended that consolidative radiation therapy be considered on a case-by-case basis for 4 to 5 sites of oligometastatic disease, driver mutation-positive oligometastatic disease without progression on up-front targeted therapy, and oligoprogressive cases. CONCLUSIONS: Although SBRT/SABR appears to be both safe and effective in treating patients with limited metastatic sites of disease, many clinical circumstances require individualized management and strong multidisciplinary discussion on account of the limited existing data.

American Radium Society Appropriate Use Criteria: Radiation Therapy for Limited-Stage SCLC 2020.

INTRODUCTION: Combined modality therapy with concurrent chemotherapy and radiation has long been the standard of care for limited-stage SCLC (LS-SCLC). However, there is controversy over best combined modality practices for LS-SCLC. To address these controversies, the American Radium Society (ARS) Thoracic Appropriate Use Criteria (AUC) Committee have developed updated consensus guidelines for the treatment of LS-SCLC. METHODS: The ARS AUC are evidence-based guidelines for specific clinical conditions that are reviewed by a multidisciplinary expert panel. The guidelines include a review and analysis of current evidence with application of consensus methodology (modified Delphi) to rate the appropriateness of treatments recommended by the panel for LS-SCLC. Agreement or consensus was defined as less than or equal to 3 rating points from the panel median. The consensus ratings and recommendations were then vetted by the ARS Executive Committee and subject to public comment before finalization. RESULTS: The ARS Thoracic AUC committee developed multiple consensus recommendations for LS-SCLC. There was strong consensus that patients with unresectable LS-SCLC should receive concurrent chemotherapy with radiation delivered either once or twice daily. For medically inoperable T1-T2N0 LS-SCLC, either concurrent chemoradiation or stereotactic body radiation followed by adjuvant chemotherapy is a reasonable treatment option. The panel continues to recommend whole-brain prophylactic cranial irradiation after response to chemoradiation for LS-SCLC. There was panel agreement that prophylactic cranial irradiation with hippocampal avoidance and programmed cell death protein-1/programmed death-ligand 1-directed immune therapy should not be routinely administered outside the context of clinical trials at this time. CONCLUSIONS: The ARS Thoracic AUC Committee provide consensus recommendations for LS-SCLC that aim to provide a groundwork for multidisciplinary care and clinical trials.

American Radium Society Appropriate Use Criteria on Radiation Therapy for Extensive-Stage SCLC.

INTRODUCTION: The standard-of-care therapy for extensive-stage SCLC has recently changed with the results of two large randomized trials revealing improved survival with the addition of immunotherapy to first-line platinum or etoposide chemotherapy. This has led to a lack of clarity around the role of consolidative thoracic radiation and prophylactic cranial irradiation in the setting of chemoimmunotherapy. METHODS: The American Radium Society Appropriate Use Criteria are evidence-based guidelines for specific clinical conditions that are reviewed by a multidisciplinary expert panel. The guidelines include a review and analysis of current evidence with the application of consensus methodology (modified Delphi) to rate the appropriateness of treatments recommended by the panel for extensive-stage SCLC. RESULTS: Current evidence supports either prophylactic cranial irradiation or surveillance with magnetic resonance imaging every 3 months for patients without evidence of brain metastases. Patients with brain metastases should receive whole-brain radiation with a recommended dose of 30 Gy in 10 fractions. Consolidative thoracic radiation can be considered in selected cases with the recommended dose ranging from 30 to 54 Gy; this recommendation was driven by expert opinion owing to the limited strength of evidence, as clinical trials addressing this question remain ongoing. CONCLUSIONS: Radiation therapy remains an integral component in the treatment paradigm for ES-SCLC.

Stereotactic Image Guided Lung Radiation Therapy for Clinical Early Stage Non-Small Cell Lung Cancer: A Long-Term Report From a Multi-Institutional Database of Patients Treated With or Without a Pathologic Diagnosis.

PURPOSE: Early stage lung cancer is treated with stereotactic body radiation therapy (SBRT) in patients who are unable or unwilling to undergo surgical resection. Some patients' comorbidities are so severe that they are unable to even undergo a biopsy. A clinical diagnosis without biopsy before SBRT has been used, but there are limited data on its efficacy. METHODS AND MATERIALS: Data on patients treated with SBRT for non-small cell lung cancer, with and without tissue confirmation, were collected from multiple institutions across Europe, Canada, and the United States. Patients with a minimum of 2 years of comprehensive follow up were selected for analysis. Treatment and patient characteristics were compared. Overall survival (OS), disease-free survival (DFS), cause-specific survival (CSS), and rates of local recurrence (LR), regional recurrence (RR), and distant metastasis (DM) were calculated and analyzed. RESULTS: A total of 701 patients were identified, of which 67% had tissue confirmation of their tumors. The 3- and 5-year outcomes for OS, CSS, and DFS were 83.8%, 93.1%, 69%, and 60.6%, 86.7%, 45.5%, respectively. The rates for LR, RR, and DM at 3 and 5 years were 6.4%, 9.3%, 14.3%, and 10.5%, 14.3%, 19.7%, respectively. There were no statistically significant differences in survival outcomes or recurrences between the biopsy and no-biopsy cohorts. CONCLUSIONS: SBRT for clinically diagnosed lung cancers is efficacious in appropriately selected patients, with similar outcomes as those with a pathologic diagnosis. Thorough clinical and radiographic evaluations in a multidisciplinary setting are critical to the management of these patients.

Cardiac Dose in Locally Advanced Lung Cancer: Results From a Statewide Consortium.

PURPOSE: The heart has been identified as a potential significant organ at risk in patients with locally advanced non-small cell lung cancer treated with radiation. Practice patterns and radiation dose delivered to the heart in routine practice in academic and community settings are unknown. METHODS AND MATERIALS: Between 2012 and 2017, 746 patients with stage III non-small cell lung cancer were treated with radiation within the statewide Michigan Radiation Oncology Quality Consortium (MROQC). Cardiac radiation dose was characterized, including mean and those exceeding historical or recently proposed Radiation Therapy Oncology Group and NRG Oncology constraints. Sites were surveyed to determine dose constraints used in practice. Patient-, anatomic-, and treatment-related associations with cardiac dose were analyzed using multivariable regression analysis and inverse probability weighting. RESULTS: Thirty-eight percent of patients had a left-sided primary, and 80% had N2 or N3 disease. Median prescription was 60 Gy (interquartile range, 60-66 Gy). Twenty-two percent of patients were prescribed 60 Gy in 2012, which increased to 62% by 2017 (P < .001). Median mean heart dose was 12 Gy (interquartile range, 5-19 Gy). The volume receiving 30 Gy (V30 Gy) exceeded 50% in 5% of patients, and V40 Gy was >35% in 3% of cases. No heart dose constraint was uniformly applied. Intensity modulated radiation therapy (IMRT) usage increased from 33% in 2012 to 86% in 2017 (P < .001) and was significantly associated with more complex cases (larger planning target volume, higher stage, and preexisting cardiac disease). In multivariable regression analysis, IMRT was associated with a lower percent of the heart receiving V30 Gy (absolute reduction = 3.0%; 95% confidence interval, 0.5%-5.4%) and V50 Gy (absolute reduction = 3.6%; 95% confidence interval, 2.4%-4.8%) but not mean dose. In inverse probability weighting analysis, IMRT was associated with 29% to 48% relative reduction in percent of the heart receiving V40-V60 Gy without increasing lung or esophageal dose or compromising planning target volume coverage. CONCLUSIONS: Within MROQC, historical cardiac constraints were met in most cases, yet 1 in 4 patients received a mean heart dose exceeding 20 Gy. Future work is required to standardize heart dose constraints and to develop treatment approaches that allow for constraints to be met without compromising other planning goals.

Optimal use of re-excision in patients diagnosed with early-stage breast cancer by excisional biopsy treated with breast-conserving therapy.

PURPOSE: The goal of the current study is to help refine guidelines for the need for re-excision and the appropriate amount of breast tissue to re-excise in patients with early breast cancer following excisional breast biopsy when treated with breast-conserving therapy (BCT). PATIENTS AND METHODS: The study population consisted of 441 patients derived from a dataset of 607 consecutive cases of stage I and II breast cancer treated with BCT, in which patients underwent primary excisional diagnostic biopsy and subsequent re-excision prior to the initiation of radiation therapy (RT). A single pathologist reviewed all specimens. Re-excision was indicated because tumor was found close to or involving the resection margin. In 333 of the 441 cases, it was possible to measure the extension of carcinoma into the re-excision specimen. Margins were classified as negative (carcinoma>4.2 mm from the margin), near (<4.2 mm from the margin) or positive. Any carcinoma identified near the final margin was quantified by width of invasive carcinoma and number of ductal carcinoma in situ (DCIS) ducts near the margin and subdivided into three distinct groups: least, intermediate, and greatest amount. These factors were then analyzed to determine the likelihood and extent of residual carcinoma in re-excision specimens. Statistical analysis was performed using Systat version 10 (SPSS Inc., Chicago, IL). RESULTS: The quantity of carcinoma near the initial biopsy margin and the invasive carcinoma-to-specimen dimension ratio demonstrated a significant association with increasing amounts of residual carcinoma at re-excision. Combination of these two variables allowed for a statistically significant (P<0.001) calculation of risk index for identifying significant residual invasive carcinoma or DCIS in the adjacent breast parenchyma at re-excision, and yielded stratification into low- (6%), intermediate- (27%), and high-risk (44%) groups. In re-excision specimens, the observed distance of carcinoma extension into adjacent breast tissue was associated with a statistically significant decrease in the ratio of the initial excisional biopsy specimen dimensions and invasive carcinoma dimensions. Combining the initial margin status with the specimen-to-invasive carcinoma maximum dimension ratio yielded an accurate predictor of the maximum distance of tumor extension. CONCLUSIONS: Evaluation of the initial excisional biopsy margin status in correlation with the invasive carcinoma-to-specimen maximum dimension ratio may be helpful for (1) identifying patients who require re-excision prior to RT and (2) predicting the quantity of additional breast tissue to excise to ensure adequate surgical margins with BCT.

Dosimetric advantages of four-dimensional adaptive image-guided radiotherapy for lung tumors using online cone-beam computed tomography.

PURPOSE: This study compares multiple planning techniques designed to improve accuracy while allowing reduced planning target volume (PTV) margins though image-guided radiotherapy (IGRT) with four-dimensional (4D) cone-beam computed tomography (CBCT). METHODS AND MATERIALS: Free-breathing planning and 4D-CBCT scans were obtained in 8 patients with lung tumors. Four plans were generated for each patient: 3D-conformal, 4D-union, 4D-offline adaptive with a single correction (offline ART), and 4D-online adaptive with daily correction (online ART). For the 4D-union plan, the union of gross tumor volumes from all phases of the 4D-CBCT was created with a 5-mm expansion applied for setup uncertainty. For offline and online ART, the gross tumor volume was delineated at the mean position of tumor motion from the 4D-CBCT. The PTV margins were calculated from the random components of tumor motion and setup uncertainty. RESULTS: Adaptive IGRT techniques provided better PTV coverage with less irradiated normal tissues. Compared with 3D plans, mean relative decreases in PTV volumes were 15%, 39%, and 44% using 4D-union, offline ART, and online ART planning techniques, respectively. This resulted in mean lung volume receiving > or = 20Gy (V20) relative decreases of 21%, 23%, and 31% and mean lung dose relative decreases of 16%, 26%, and 31% for the 4D-union, 4D-offline ART, and 4D-online ART, respectively. CONCLUSIONS: Adaptive IGRT using CBCT is feasible for the treatment of patients with lung tumors and significantly decreases PTV volume and dose to normal tissues, allowing for the possibility of dose escalation. All analyzed 4D planning strategies resulted in improvements over 3D plans, with 4D-online ART appearing optimal.

Image-guided radiotherapy via daily online cone-beam CT substantially reduces margin requirements for stereotactic lung radiotherapy.

PURPOSE: To determine treatment accuracy and margins for stereotactic lung radiotherapy with and without cone-beam CT (CBCT) image guidance. METHODS AND MATERIALS: Acquired for the study were 308 CBCT of 24 patients with solitary peripheral lung tumors treated with stereotactic radiotherapy. Patients were immobilized in a stereotactic body frame (SBF) or alpha-cradle and treated with image guidance using daily CBCT. Four (T1) or five (T2/metastatic) 12-Gy fractions were prescribed to the planning target volume (PTV) edge. The PTV margin was >or=5 mm depending on a pretreatment estimate of tumor excursion. Initial daily setup was according to SBF coordinates or tattoos for alpha-cradle cases. A CBCT was performed and registered to the planning CT using soft tissue registration of the target. The initial setup error/precorrection position, was recorded for the superior-inferior, anterior-posterior, and medial-lateral directions. The couch was adjusted to correct the tumor positional error. A second CBCT verified tumor position after correction. Patients were treated in the corrected position after the residual errors were

Clinical implications of defining the gross tumor volume with combination of CT and 18FDG-positron emission tomography in non-small-cell lung cancer.

PURPOSE: To compare the planning target volume (PTV) definitions for computed tomography (CT) vs. positron emission tomography (PET) in non-small-cell lung cancer (NSCLC). METHODS AND MATERIALS: A total of 21 patients with NSCLC underwent three-dimensional conformal radiotherapy planning. All underwent a staging F-18 fluorodeoxyglucose-position emission tomography (18FDG-PET) scan and underwent treatment simulation using CT plus a separate planning 18FDG-PET scan. Three sets of target volumes were defined: Set 1, CT volumes (CT tumor + staging PET nodal disease); Set 2, PET volumes (planning PET tumor {gross tumor volume (GTV) = [(0.3069 x mean standardized uptake value) + 0.5853])}; Set 3, composite CT-PET volumes (fused CT-PET tumor). Sets 1 and 2 were compared using a matching index. Three-dimensional conformal radiotherapy plans were created using the Set 1 (CT) volumes; and coverage of the Set 3 (composite) volumes was evaluated. Separate three-dimensional conformal radiotherapy plans were designed for the Set 3 volumes. RESULTS: For the primary tumor GTV, the Set 1 (CT) volume was larger than the Set 2 (PET) volume in 48%, smaller in 33%, and equal in 19%. The mean matching index was 0.65 (35% CT-PET mismatch). Although quantitatively similar, the volumes differed qualitatively. The Set 3 (composite) volume was larger than either CT or PET alone in 62%, smaller in 24%, and equal in 14%. The dose-volume histogram parameters did not differ among the plans for Set 1 (CT) vs. Set 3 (composite) volumes. Small portions of the Set 3 PTV were significantly underdosed in 40% of cases using the CT-only plan. CONCLUSION: Computed tomography and PET are complementary and should be obtained in the treatment position and fused to define the GTV for NSCLC. Although the quantitative absolute target volume is sometimes similar, the qualitative target locations can be substantially different, leading to underdosage of the target when planning is done using CT alone without PET fusion.

Clinicopathologic analysis of microscopic extension in lung adenocarcinoma: defining clinical target volume for radiotherapy.

PURPOSE: To determine the gross tumor volume (GTV) to clinical target volume margin for non-small-cell lung cancer treatment planning. METHODS: A total of 35 patients with Stage T1N0 adenocarcinoma underwent wedge resection plus immediate lobectomy. The gross tumor size and microscopic extension distance beyond the gross tumor were measured. The nuclear grade and percentage of bronchoalveolar features were analyzed for association with microscopic extension. The gross tumor dimensions were measured on a computed tomography (CT) scan (lung and mediastinal windows) and compared with the pathologic dimensions. The potential coverage of microscopic extension for two different lung stereotactic radiotherapy regimens was evaluated. RESULTS: The mean microscopic extension distance beyond the gross tumor was 7.2 mm and varied according to grade (10.1, 7.0, and 3.5 mm for Grade 1 to 3, respectively, p < 0.01). The 90th percentile for microscopic extension was 12.0 mm (13.0, 9.7, and 4.4 mm for Grade 1 to 3, respectively). The CT lung windows correlated better with the pathologic size than did the mediastinal windows (gross pathologic size overestimated by a mean of 5.8 mm; composite size [gross plus microscopic extension] underestimated by a mean of 1.2 mm). For a GTV contoured on the CT lung windows, the margin required to cover microscopic extension for 90% of the cases would be 9 mm (9, 7, and 4 mm for Grade 1 to 3, respectively). The potential microscopic extension dosimetric coverage (55 Gy) varied substantially between the stereotactic radiotherapy schedules. CONCLUSION: For lung adenocarcinomas, the GTV should be contoured using CT lung windows. Although a GTV based on the CT lung windows would underestimate the gross tumor size plus microscopic extension by only 1.2 mm for the average case, the clinical target volume expansion required to cover the microscopic extension in 90% of cases could be as large as 9 mm, although considerably smaller for high-grade tumors. Fractionation significantly affects the dosimetric coverage of microscopic extension.

Use of individual fraction size data from 3756 patients to directly determine the alpha/beta ratio of prostate cancer.

PURPOSE: To examine the effect of fraction size and total dose of radiation on recurrence of localized prostate cancer. METHODS AND MATERIALS: A total of 3756 patients treated with radiation monotherapy at three institutions were analyzed, including 185 high-dose-rate brachytherapy (HDRB) boost patients. The 5th to 95th centiles of external beam radiotherapy (EBRT) fraction sizes and doses were 1.8 to 2.86 Gy, and 57.4 to 77.4 Gy, respectively, and HDRB fractional doses were between 5.5 and 12 Gy, totaling 147 unique fractionation schedules. Failure was defined by one biochemical (nadir + 2 ng/ml) and two advanced disease endpoints. The alpha/beta ratios were estimated via a proportional hazards model stratified by risk severity and institution. RESULTS: The alpha/beta ratio using biochemical recurrence was 3.7 Gy (95% confidence interval [95% CI], 1.1, infinity Gy) for EBRT-only cases and 2.6 Gy (95% CI, 0.9, 4.8 Gy) after the addition of HDRB data. This estimate was highly dependent on an HDRB homogeneity correction factor (120% HDRB dose increase; alpha/beta ratio 4.5 Gy, 95% CI 1.6, 8.7 Gy). A 5-Gy increase in total dose reduced the hazard of failure by 16% (95% CI 11, 21%, p < 0.0001), and had more impact as follow-up matured (p < 0.0003). The clinically advanced endpoints concurred with the biochemical failure results, albeit with less precision. CONCLUSIONS: This study supports the concept that the alpha/beta ratio of prostate cancer is low, although considerable uncertainty remains in the estimated value. Outcome data from EBRT studies using substantially higher doses per fraction are needed to show increased precision in these estimates.