Malcolm D. Mattes

Routine Histopathologic Characteristics Can Predict Oncotype DXTM Recurrence Score in Subsets of Breast Cancer Patients

This study assessed whether routine pathologic parameters could predict Oncotype DXTM recurrence score (RS) in 72 breast cancers diagnosed from 2008–2012. Comparing patients with low RS (0–17) vs. intermediate RS (18–30) vs. high RS (>30), the mean Nottingham score increased (5.5 vs. 6.3 vs. 7.2, respectively, p = .001) and the mean PR Allred score decreased (6.7 vs. 4.9 vs. 3.3, respectively, p = .001). A high RS was least likely for low-grade tumors (0% had high RS, p = .005), and strong PR positivity (9% had high RS, p = .017). A low RS was least likely for cancers that were both high grade and PR weak/negative.

Model-guided therapy for hepatocellular carcinoma: a role for information technology in predictive, preventive and personalized medicine

Predictive, preventive and personalized medicine (PPPM) may have the potential to eventually improve the nature of health care delivery. However, the tools required for a practical and comprehensive form of PPPM that is capable of handling the vast amounts of medical information that is currently available are currently lacking. This article reviews a rationale and method for combining and integrating diagnostic and therapeutic management with information technology (IT), in a manner that supports patients through their continuum of care. It is imperative that any program devised to explore and develop personalized health care delivery must be firmly rooted in clinically confirmed and accepted principles and technologies. Therefore, a use case, relating to hepatocellular carcinoma (HCC), was developed. The approach to the management of medical information we have taken is based on model theory and seeks to implement a form of model-guided therapy (MGT) that can be used as a decision support system in the treatment of patients with HCC. The IT structures to be utilized in MGT include a therapy imaging and model management system (TIMMS) and a digital patient model (DPM). The system that we propose will utilize patient modeling techniques to generate valid DPMs (which factor in age, physiologic condition, disease and co-morbidities, genetics, biomarkers and responses to previous treatments). We may, then, be able to develop a statistically valid methodology, on an individual basis, to predict certain diseases or conditions, to predict certain treatment outcomes, to prevent certain diseases or complications and to develop treatment regimens that are personalized for that particular patient. An IT system for predictive, preventive and personalized medicine (ITS-PM) for HCC is presented to provide a comprehensive system to provide unified access to general medical and patient-specific information for medical researchers and health care providers from different disciplines including hepatologists, gastroenterologists, medical and surgical oncologists, liver transplant teams, interventional radiologists and radiation oncologists. The article concludes with a review providing an outlook and recommendations for the application of MGT to enhance the medical management of HCC through PPPM.

Breast Cancer Subtype as a Predictor of Lymph Node Metastasis according to the SEER Registry

Purpose Breast cancer subtype correlates with response to systemic therapy and overall survival (OS), but its impact on lymphatic spread is incompletely understood. In this study, we used the Surveillance, Epidemiology, and End Results registry to assess whether the subtype can predict the presence of nodal metastasis or advanced nodal stage in breast cancer. Methods A total of 7,274 eligible patients diagnosed with T1-3 infiltrating ductal carcinoma with known estrogen or progesterone hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) status, who underwent surgical excision of the primary tumor and pathologic lymph node evaluation, were included in this analysis. Patients were categorized into four breast cancer subtypes: HR+/HER2-; HR+/HER2+; HR-/HER2+; and HR-/HER2-. Binary logistic regression analysis was used to determine whether breast cancer subtype, tumor size, tumor grade, patient race, and patient age at diagnosis are independently predictive of lymph node positivity or advanced nodal stage. The Pearson chi-square test was used to determine whether progesterone receptor (PR) status had an impact on the incidence of lymph node positivity in estrogen receptor (ER) positive patients. Results Independent predictors of nodal positivity included breast cancer subtype (p=0.040), tumor size (p<0.001), tumor grade (p<0.001), and patient age (p<0.001), whereas only tumor size (p<0.001), grade (p=0.001), and patient age (p=0.005) predicted advanced nodal stage. Triple-negative cancers had a significantly lower risk of nodal positivity than the HR+/HER2- subtype (odds ratio, 0.686; p=0.004), but no other significant differences between subtypes were observed. There was also no difference in lymph node positivity between PR+ and PR- tumors amongst ER+/HER2- (p=0.228) or ER+/HER2+ tumors (p=0.713). Conclusion The HR+/HER2-breast cancer subtype has a higher rate of lymph node involvement at diagnosis than the triple-negative subtype. These findings may play a role in guiding regional management considerations if confirmed in further studies.

Reflections on Hope and Its Implications for End-of-Life Care

Physicians caring for individuals with life‐altering, incurable illnesses often have a desire to convey a sense of hope while also helping their patients prepare for the end of life to minimize unnecessary suffering and grief. Unfortunately, in the United States, most people receive more‐aggressive treatments toward the end of life than studies would suggest that they desire. This reflects the challenging task of balancing optimism and realism, and how providing a false sense of hope for a cure for too long a time while avoiding advance care planning may contribute significantly to the problem. This article explores the interplay of hope and advance care planning, and suggests a need for excellent individualized communication in the setting of advanced cancer to improve end‐of‐life care.

Ratio of Lymph Node to Primary Tumor SUV on PET/CT Accurately Predicts Nodal Malignancy in Non–Small-Cell Lung Cancer

UNLABELLED Thoracic lymph nodes with marginally elevated maximum standardized uptake value (SUVmax) on PET/CT a diagnostic challenge in staging non-small-cell lung cancer. We evaluated the ratio of lymph node to primary tumor SUVmax (SUVN/T) in predicting nodal malignancy among 132 sampled nodes from 85 patients both a primary tumor SUVmax > 2.5 and LN SUVmax 2.0 to 6.0. SUVN/T was more accurate than SUVmax for this subset of patients. INTRODUCTION/BACKGROUND Among non-small-cell lung cancers with appreciable functional activity, positron emission tomography/computed tomography (PET/CT) is the most accurate imaging modality for clinical staging. However, lymph nodes (LN) with marginally elevated standardized uptake value (SUV) present a diagnostic challenge. In this retrospective study, we hypothesized that normalizing the LN SUV by using the ratio of the LN to primary tumor SUVmax (SUVN/T) may be a better predictor of nodal malignancy than using SUVmax alone for nodes with low to intermediate SUV. PATIENTS AND METHODS We identified 172 patients with newly diagnosed non-small-cell lung cancer who underwent pathologic LN staging and PET/CT within 31 days before biopsy. Receiver operating characteristic curves with area under the curve (AUC) calculations were used to evaluate SUVmax and SUVN/T for their ability to predict nodal malignancy for both the entire cohort of 504 LNs and a subset of 132 LNs from 85 patients who had both primary tumor SUVmax > 2.5 and LN SUVmax 2.0 to 6.0. RESULTS In patients with primary tumor SUVmax > 2.5 and LN SUVmax 2.0 to 6.0, SUVN/T was significantly more accurate in predicting nodal malignancy (AUC, 0.846; 95% confidence interval, 0.775-0.917) than SUVmax (AUC, 0.653; 95% confidence interval, 0.548-0.759). The optimal cutoff value of SUVN/T to predict nodal malignancy was 0.28 (90% sensitivity, 68% specificity). Sensitivity was > 95% for SUVN/T < 0.21, whereas specificity was > 95% for SUVN/T > 0.50. CONCLUSION The ratio of LN SUV to primary tumor SUV on PET/CT is more accurate than SUVmax when assessing nodes of low to intermediate SUV.

Attitudes of radiation oncologists toward palliative and supportive care in the United States: Report on national membership survey by the American Society for Radiation Oncology (ASTRO)

PURPOSE Radiation oncologists are frequently involved in providing palliative and supportive care (PSC) for patients with advanced cancers through delivery of palliative radiation. Whether they are confident in their ability to assess and initiate treatments for pain, nonpain, and psychosocial distress is unknown. The American Society for Radiation Oncology surveyed its practicing members in the United States on self-assessment of their primary PSC skills and access to continuing medical education on PSC. METHODS We electronically surveyed 4093 practicing radiation oncologists in the United States. The survey consisted of 16-questions in 5 sections1: demographics,2 PSC training,3 domains of PSC,4 perceived barriers as a radiation oncologist to initiate advanced care planning, and5 discussion of prognosis. RESULTS The survey was e-mailed to 4093 American Society for Radiation Oncology members, and 649 responses were received (response rate 16%). The majority (91%) of radiation oncologists surveyed believe PSC is an important competency for radiation oncologists. Most radiation oncologists reported that they are moderately confident in their ability to assess and manage pain and gastrointestinal symptoms, but less confident in their ability to manage anorexia, anxiety, and depression. Despite areas of decreased confidence, a large number (42%) of radiation oncologists do not receive any additional PSC education beyond their residency training. Lastly, a perceived fear of upsetting referring medical oncologists and lack of clinic time are concerns for radiation oncologists who may want to initiate goals of care/advance care planning discussions with patients and their families. CONCLUSION Radiation oncologists are more confident in their ability to assess and manage pain than in their ability to manage depression, anxiety, anorexia, and fatigue. There is a need for increasing continuing medical educational efforts in PSC for practicing radiation oncologists, and strengthening PSC training in residency programs.

External beam radiation therapy for small cell carcinoma of the urinary bladder

PURPOSE Small cell carcinoma of the urinary bladder (SCCB) is rare. We report our experience using definitive external beam radiation therapy (EBRT) as part of multimodality management of SCCB. METHODS AND MATERIALS Nineteen patients with locoregional SCCB were treated at our institution with EBRT between January 1994 and September 2012. Five patients had radiographic nodal disease. Eighteen patients received neoadjuvant (17/19; 89%) or concurrent (11/19: 58%) platinum-based chemotherapy. Acute (<90 days) and late (>90 days) toxicity was recorded using Common Terminology Criteria for Adverse Events, version 4. The Kaplan-Meier method was used for survival analysis and a log-rank test used to compare subsets of patients. RESULTS Median follow-up was 26 months. Three patients had in-bladder recurrence (2-year local recurrence, 25%), 2 being noninvasive and successfully managed with transurethral resection and the third being invasive but managed with chemotherapy alone due to simultaneous distant metastases. No patient underwent salvage cystectomy. Six patients had recurrence distantly (2-year distant recurrence, 40%), predominantly bone metastases (n = 3). No patients developed brain metastases. Actuarial 2-year disease-free and overall survival was 51% and 78%, respectively. The 2-year distant metastasis-free survival for node-negative and node-positive patients was 76% and 26%, respectively (P = .04). The 2-year incidence of distant metastases for patients receiving ≥4 cycles of doublet chemotherapy was 27%, compared with 75% with less chemotherapy (P = .01). The incidence of grade ≥2 acute and late genitourinary or gastrointestinal toxicity was 69% and 7%, respectively. CONCLUSIONS Definitive chemoradiation for locoregional SCCB is well tolerated, with encouraging local control and overall survival at 2 years.

A predictive model to guide management of the overlap region between target volume and organs at risk in prostate cancer volumetric modulated arc therapy

Purpose The goal of this study is to determine whether the magnitude of overlap between planning target volume (PTV) and rectum (Rectumoverlap) or PTV and bladder (Bladderoverlap) in prostate cancer volumetric-modulated arc therapy (VMAT) is predictive of the dose-volume relationships achieved after optimization, and to identify predictive equations and cutoff values using these overlap volumes beyond which the Quantitative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) dose-volume constraints are unlikely to be met. Materials and Methods Fifty-seven patients with prostate cancer underwent VMAT planning using identical optimization conditions and normalization. The PTV (for the 50.4 Gy primary plan and 30.6 Gy boost plan) included 5 to 10 mm margins around the prostate and seminal vesicles. Pearson correlations, linear regression analyses, and receiver operating characteristic (ROC) curves were used to correlate the percentage overlap with dose-volume parameters. Results The percentage Rectumoverlap and Bladderoverlap correlated with sparing of that organ but minimally impacted other dose-volume parameters, predicted the primary plan rectum V45 and bladder V50 with R2 = 0.78 and R2 = 0.83, respectively, and predicted the boost plan rectum V30 and bladder V30 with R2 = 0.53 and R2 = 0.81, respectively. The optimal cutoff value of boost Rectumoverlap to predict rectum V75 >15% was 3.5% (sensitivity 100%, specificity 94%, p < 0.01), and the optimal cutoff value of boost Bladderoverlap to predict bladder V80 >10% was 5.0% (sensitivity 83%, specificity 100%, p < 0.01). Conclusion The degree of overlap between PTV and bladder or rectum can be used to accurately guide physicians on the use of interventions to limit the extent of the overlap region prior to optimization.

The incidence of pelvic and para-aortic lymph node metastasis in uterine papillary serous and clear cell carcinoma according to the SEER registry

Objective In this study we utilized the Surveillance, Epidemiology and End-Results (SEER) registry to identify risk factors for lymphatic spread and determine the incidence of pelvic and para-aortic lymph node metastases in patients with uterine papillary serous carcinoma (UPSC) and uterine clear cell carcinoma (UCCC) who underwent complete surgical staging and lymph node dissection. Methods Nine hundred seventy-two eligible patients diagnosed between 1998 to 2009 with International Federation of Gynecology and Obstetrics (FIGO) 1988 stage IA-IVA UPSC (n=685) or UCCC (n=287) were identified for analysis. Binomial logistic regression was used to determine risk factors for lymph node metastasis, with the incidence of pelvic and para-aortic lymph node metastases reported for each FIGO primary tumor stage. The Cox proportional hazards regression model was used to determine factors associated with overall survival. Results FIGO primary tumor stage was the only independent risk factor for lymph node metastasis (p<0.01). The incidence of pelvis-only and para-aortic lymph node involvement according to the FIGO primary tumor stage were as follows: IA (2.3%/3.8%), IB (7.5%/5.2%), IC (22.5%/16.9%), IIA (20.8%/13.2%), IIB (25.7%/14.9%), and III/IV (25.7%/24.3%). Prognostic factors for overall survival included lymph node involvement (hazard ratio [HR], 1.42; 95% confidence interval [CI], 1.09 to 1.85; p<0.01), patient age >60 years (HR, 1.70; 95% CI, 1.21 to 2.41; p<0.01), and advanced FIGO primary tumor stage (p<0.01). Tumor grade, histologic subtype, and patient race did not predict for either lymph node metastasis or overall survival. Conclusion There is a high incidence of both pelvic and para-aortic lymph node metastases for FIGO stages IC and above uterine papillary serous and clear cell carcinomas, suggesting a potential role for lymph node-directed therapy for these patients.

A Predictive Model for Lymph Node Involvement with Malignancy on PET/CT in Non–Small-Cell Lung Cancer

Introduction: Accurate assessment of lymph node (LN) involvement with malignancy is critical to staging and management of non–small-cell lung cancer. The goal of this retrospective study was to determine the tumor and imaging characteristics independently associated with malignant involvement of LNs visualized on positron emission tomography/computed tomography (PET/CT). Methods: From 2002 to 2011, 172 patients with newly diagnosed non–small-cell lung cancer underwent PET/CT within 31 days before LN biopsy. Among these patients, 504 anatomically defined, pathology-confirmed LNs were visualized on PET/CT. Logistic regression analysis was used to determine the associations between nodal involvement with malignancy and several clinical and imaging variables, including tumor histology, tumor grade, LN risk category in relation to the primary tumor location, pathologic findings from additional biopsied LNs, interval between PET/CT and biopsy, primary tumor largest dimension, primary tumor standardized uptake value (SUVmax), LN short-axis dimension, and LN SUVmax. Results: On univariate analysis, adenocarcinoma histology (p = 0.010), high LN risk category (p < 0.001), larger LN short-axis dimension (p < 0.001), and higher LN SUVmax (p < 0.001) all correlated with nodal involvement. On multivariate analysis, adenocarcinoma histology (p = 0.003), high LN risk category (p = 0.005), and higher LN SUVmax (p < 0.001) correlated with nodal involvement, whereas LN short-axis dimension was no longer statistically significant (p = 0.180). A nomogram developed for clinical application based on this analysis had excellent concordance between predicted and observed results (concordance index, 0.95). Conclusion: Adenocarcinoma histology, higher LN SUVmax, and higher LN risk category independently correlate with nodal involvement with malignancy and may be used in a model to accurately predict the risk of a node’s involvement with malignancy.