D.N. Ayala-Peacock

A nomogram for predicting distant brain failure in patients treated with gamma knife stereotactic radiosurgery without whole brain radiotherapy

BACKGROUND We review our single institution experience to determine predictive factors for early and delayed distant brain failure (DBF) after radiosurgery without whole brain radiotherapy (WBRT) for brain metastases. MATERIALS AND METHODS Between January 2000 and December 2010, a total of 464 patients were treated with Gamma Knife stereotactic radiosurgery (SRS) without WBRT for primary management of newly diagnosed brain metastases. Histology, systemic disease, RPA class, and number of metastases were evaluated as possible predictors of DBF rate. DBF rates were determined by serial MRI. Kaplan-Meier method was used to estimate rate of DBF. Multivariate analysis was performed using Cox Proportional Hazard regression. RESULTS Median number of lesions treated was 1 (range 1-13). Median time to DBF was 4.9 months. Twenty-seven percent of patients ultimately required WBRT with median time to WBRT of 5.6 months. Progressive systemic disease (χ(2)= 16.748, P < .001), number of metastases at SRS (χ(2) = 27.216, P < .001), discovery of new metastases at time of SRS (χ(2) = 9.197, P < .01), and histology (χ(2) = 12.819, P < .07) were factors that predicted for earlier time to distant failure. High risk histologic subtypes (melanoma, her2 negative breast, χ(2) = 11.020, P < .001) and low risk subtypes (her2 + breast, χ(2) = 11.343, P < .001) were identified. Progressive systemic disease (χ(2) = 9.549, P < .01), number of brain metastases (χ(2) = 16.953, P < .001), minimum SRS dose (χ(2) = 21.609, P < .001), and widespread metastatic disease (χ(2) = 29.396, P < .001) were predictive of shorter time to WBRT. CONCLUSION Systemic disease, number of metastases, and histology are factors that predict distant failure rate after primary radiosurgical management of brain metastases.

Clinical and economic outcomes of patients with brain metastases based on symptoms: An argument for routine brain screening of those treated with upfront radiosurgery

Insurers have started to deny reimbursement for routine brain surveillance with magnetic resonance imaging (MRI) after stereotactic radiosurgery (SRS) for brain metastases in favor of symptom‐prompted imaging. The authors investigated the clinical and economic impact of symptomatic versus asymptomatic metastases and related these findings to the use of routine brain surveillance.

Prediction of new brain metastases after radiosurgery: validation and analysis of performance of a multi-institutional nomogram

Stereotactic radiosurgery (SRS) without whole brain radiotherapy (WBRT) for brain metastases can avoid WBRT toxicities, but with risk of subsequent distant brain failure (DBF). Sole use of number of metastases to triage patients may be an unrefined method. Data on 1354 patients treated with SRS monotherapy from 2000 to 2013 for new brain metastases was collected across eight academic centers. The cohort was divided into training and validation datasets and a prognostic model was developed for time to DBF. We then evaluated the discrimination and calibration of the model within the validation dataset, and confirmed its performance with an independent contemporary cohort. Number of metastases (≥8, HR 3.53 p = 0.0001), minimum margin dose (HR 1.07 p = 0.0033), and melanoma histology (HR 1.45, p = 0.0187) were associated with DBF. A prognostic index derived from the training dataset exhibited ability to discriminate patients’ DBF risk within the validation dataset (c-index = 0.631) and Heller’s explained relative risk (HERR) = 0.173 (SE = 0.048). Absolute number of metastases was evaluated for its ability to predict DBF in the derivation and validation datasets, and was inferior to the nomogram. A nomogram high-risk threshold yielding a 2.1-fold increased need for early WBRT was identified. Nomogram values also correlated to number of brain metastases at time of failure (r = 0.38, p < 0.0001). We present a multi-institutionally validated prognostic model and nomogram to predict risk of DBF and guide risk-stratification of patients who are appropriate candidates for radiosurgery versus upfront WBRT.

Is a Clinical Target Volume (CTV) Necessary in the Treatment of Lung Cancer in the Modern Era Combining 4-D Imaging and Image-guided Radiotherapy (IGRT)?

Objective: We hypothesized that omission of clinical target volumes (CTV) in lung cancer radiotherapy would not compromise control by determining retrospectively if the addition of a CTV would encompass the site of failure. Methods: Stage II-III patients were treated from 2009-2012 with daily cone-beam imaging and a 5 mm planning target volume (PTV) without a CTV. PTVs were expanded 1 cm and termed CTVretro. Recurrences were scored as 1) within the PTV, 2) within CTVretro, or 3) outside the PTV. Locoregional control (LRC), distant control (DC), progression-free survival (PFS), and overall survival (OS) were estimated. Result: Among 110 patients, Stage IIIA 57%, IIIB 32%, IIA 4%, and IIB 7%. Eighty-six percent of Stage III patients received chemotherapy. Median dose was 70 Gy (45-74 Gy) and fraction size ranged from 1.5-2.7 Gy. Median follow-up was 12 months, median OS was 22 months (95% CI 19-30 months), and LRC at two years was 69%. Fourteen local and eight regional events were scored with two CTVretro failures equating to a two-year CTV failure-free survival of 98%. Conclusion: Omission of a 1 cm CTV expansion appears feasible based on only two events among 110 patients and should be considered in radiation planning.

Classification for long-term survival in oligometastatic patients treated with ablative radiotherapy: A multi-institutional pooled analysis

Background Radiotherapy is increasingly used to treat oligometastatic patients. We sought to identify prognostic criteria in oligometastatic patients undergoing definitive hypofractionated image-guided radiotherapy (HIGRT). Methods Exclusively extracranial oligometastatic patients treated with HIGRT were pooled. Characteristics including age, sex, primary tumor type, interval to metastatic diagnosis, number of treated metastases and organs, metastatic site, prior systemic therapy for primary tumor treatment, prior definitive metastasis-directed therapy, and systemic therapy for metastasis associated with overall survival (OS), progression-free survival (PFS), and treated metastasis control (TMC) were assessed by the Cox proportional hazards method. Recursive partitioning analysis (RPA) identified prognostic risk strata for OS and PFS based on pretreatment factors. Results 361 patients were included. Primary tumors included non-small cell lung (17%), colorectal (19%), and breast cancer (16%). Three-year OS was 56%, PFS was 24%, and TMC was 72%. On multivariate analysis, primary tumor, interval to metastases, treated metastases number, and mediastinal/hilar lymph node, liver, or adrenal metastases were associated with OS. Primary tumor site, involved organ number, liver metastasis, and prior primary disease chemotherapy were associated with PFS. OS RPA identified five classes: class 1: all breast, kidney, or prostate cancer patients (BKP) (3-year OS 75%, 95% CI 66–85%); class 2: patients without BKP with disease-free interval of 75+ months (3-year OS 85%, 95% CI 67–100%); class 3: patients without BKP, shorter disease-free interval, ≤ two metastases, and age < 62 (3-year OS 55%, 95% CI 48–64%); class 4: patients without BKP, shorter disease-free interval, ≥ three metastases, and age < 62 (3-year OS 38%, 95% CI 24–60%); class 5: all others (3-year OS 13%, 95% CI 5–35%). Higher biologically effective dose (BED) (p < 0.01) was associated with OS. Conclusions We identified clinical factors defining oligometastatic patients with favorable outcomes, who we hypothesize are most likely to benefit from metastasis-directed therapy.

Image guided radiation therapy may result in improved local control in locally advanced lung cancer patients

PURPOSE Image guided radiation therapy (IGRT) is designed to ensure accurate and precise targeting, but whether improved clinical outcomes result is unknown. METHODS AND MATERIALS A retrospective comparison of locally advanced lung cancer patients treated with and without IGRT from 2001 to 2012 was conducted. Median local failure-free survival (LFFS), regional, locoregional failure-free survival (LRFFS), distant failure-free survival, progression-free survival, and overall survival (OS) were estimated. Univariate and multivariate models assessed the association between patient- and treatment-related covariates and local failure. RESULTS A total of 169 patients were treated with definitive radiation therapy and concurrent chemotherapy with a median follow-up of 48 months in the IGRT cohort and 96 months in the non-IGRT cohort. IGRT was used in 36% (62 patients) of patients. OS was similar between cohorts (2-year OS, 47% vs 49%, P = .63). The IGRT cohort had improved 2-year LFFS (80% vs 64%, P = .013) and LRFFS (75% and 62%, P = .04). Univariate analysis revealed IGRT and treatment year improved LFFS, whereas group stage, dose, and positron emission tomography/computed tomography planning had no impact. IGRT remained significant in the multivariate model with an adjusted hazard ratio of 0.40 (P = .01). Distant failure-free survival (58% vs 59%, P = .67) did not differ significantly. CONCLUSION IGRT with daily cone beam computed tomography confers an improvement in the therapeutic ratio relative to patients treated without this technology.

A Pilot 11C-Choline PET-CT Imaging Study in Patients With Locally Advanced Esophageal Cancer.

Purpose/Objectives: As concomitant chemoradiation followed by esophagectomy has become standard treatment for locally advanced esophageal cancer, there has been increasing emphasis on identifying a reliable imaging modality to assess treatment response. Given the high false negative and false positive findings with 18F-FDG-PET in the post-treatment setting, many have sought to pursue other radiopharmaceuticals that could potentially better delineate sites of malignancy. Choline, a component of the key cell membrane building block phosphatidylcholine, has emerged as a potential useful radiotracer target for PET/CT imaging in evaluating treatment-response after neoadjuvant chemoradiation. Materials/Methods: Eight eligible patients were selected to undergo baseline and post-treatment 11-C Choline PET/CT imaging. Treatmentrelated changes seen on 11-C Choline PET were then compared to pathologic, radiographic and/or clinical follow-up data. Results: On review of our small series, the observed pCR rate was 25%. Six of the eight patients had 11C Choline PET imaging that correlated with their overall clinical outcomes, as defined by pathology and/or follow-up imaging. Two of eight patients had resolution of their primary lesion following treatment, as visualized on 11-C Choline PET. Neither patient went on to surgery, but both had confirmed negative post-treatment EGD pathology and corresponding negative conventional imaging. Two patients exhibited partial responses to therapy, as seen on 11-C Choline PET, which was confirmed on surgical pathology. A single patient was found to have unchanged disease burden on post-treatment 11-C imaging with subsequent conventional follow up concordant with stable disease. On review of the eight patients, there was a greater difference in preand post-treatment primary lesion SUV observed in patients who reached a CR on 11-C imaging (SUV 7.8) as compared to those who reached PR/SD on 11-C imaging (SUV 2.5). Conclusions: To our knowledge, this is the only prospective pilot study investigating the use of 11-Choline PET/CT for response assessment in locally advanced esophageal cancer treated with neoadjuvant chemoradiation. Although no correlation between SUVmax and pathologic response could be established with such a small cohort, the overall findings support development of a larger trial to investigate the sensitivity, specificity, and positive and negative predictive values of 11C Choline PET/CT for neoadjuvant treatment assessment in esophageal cancer.

Multi-institutional competing risks analysis of distant brain failure and salvage patterns after upfront radiosurgery without whole brain radiotherapy for brain metastasis

Background In this study, we use a competing risks analysis to assess factors predictive of early-salvage whole brain radiotherapy (WBRT) and early death after upfront stereotactic radiosurgery (SRS) alone for brain metastases in an attempt to identify populations that benefit less from upfront SRS. Patients and methods Patients from eight academic centers were treated with SRS for brain metastasis. Competing risks analysis was carried out for distant brain failure (DBF) versus death prior to DBF as well as for salvage SRS versus salvage WBRT versus death prior to salvage. Linear regression was used to determine predictors of the number of brain metastases at initial DBF (nDBF). Results A total of 2657 patients were treated with upfront SRS alone. Multivariate analysis (MVA) identified an increased hazard of DBF associated with increasing number of brain metastases (P < 0.001), lowest SRS dose received (P < 0.001), and melanoma histology (P < 0.001), while there was a decreased hazard of DBF associated with increasing age (P < 0.001), KPS < 70 (P < 0.001), and progressive systemic disease (P = 0.004). MVA for first salvage SRS versus WBRT versus death prior to salvage revealed an increased hazard of first salvage WBRT seen with increasing number of brain metastases (P < 0.001) and a decreased hazard with widespread systemic disease (P = 0.002) and increasing age (P < 0.001). Variables associated with nDBF included age (P = 0.02), systemic disease status (P = 0.03), melanoma histology (P = 0.05), and initial number of brain metastases (P < 0.001). Conclusions Patients with a higher initial number of brain metastases were more likely to experience DBF, have a higher nDBF, and receive early-salvage WBRT, while patients who were older, had lower KPS, or had more systemic disease were more likely to experience death prior to DBF or salvage WBRT.