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The Role of Bisphosphonates in Breast Cancer

Richard L. Theriault

Breast cancer frequently metastasizes to bone. Metastases result in skeletal morbidity including pathologic fractures, the need for radiation or surgery to bone, spinal cord compression and hypercalcemia. The pathophysiology of bone destruction is related to activation of osteoclasts by tumor-derived and bone marrow microenvironmental factors. One prominent osteoclast–activating factor associated with breast cancer is parathyroid hormone-related peptide (PTHrP). Bisphosphonates have been shown to impair osteoclast activity by decreasing recruitment from the monocyte macrophage cell line, inhibiting osteoclast function at the bone site and causing osteoclasts to undergo apoptosis. Clinical studies with bisphosphonates show an improvement in the control of hypercalcemia and a reduction in skeletal related morbidity with administration of pamidronate and zoledronic acid. Bisphosphonates have become the standard of care for osteolytic metastases associated with breast cancer. Recent data with zoledronic acid found that skeletal related morbidity may be reduced regardless of the radiographic picture of skeletal metastases. Thus, zoledronic acid may be valuable in osteolytic and osteoblastic disease as well as in disease with an osteolytic or osteoblastic radiographic appearance. In breast cancer with osteolytic disease, zoledronic acid may be more effective than pamidronate in reducing skeletal morbidity and prolonging the time to first skeletal event.

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Aromatase Inhibitors in Postmenopausal Breast Cancer Patients

Alyssa G. Rieber and Richard L. Theriault

Aromatase inhibitors (AIs) have greatly enriched the treatment of hormone receptor-positive breast cancer in postmenopausal patients. Before the introduction of the well-tolerated third-generation AIs, tamoxifen was the mainstay of endocrine therapy for hormone receptor-positive breast cancer. Many clinical trials have shown the superiority of AIs compared with tamoxifen in adjuvant breast cancer treatment, as well as their benefit in metastatic breast cancer. NCCN guidelines recommendations for their use are based on the evidence provided by these clinical trials. This discussion reviews the evidence supporting the current guidelines for use of AI therapy in the treatment of hormone receptor-positive postmenopausal breast cancer patients.

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The First Documented Case of High-Grade Synovial Cell Sarcoma of the Rectum

Richard B. Hostetter, Min Yan, Houman Vaghefi, Kenneth Pennington, and Gary Cornette

A patient presented with signs and symptoms of tenesmus, urgency, and rectal bleeding that she had been experiencing over the course of several months. Full endoscopic evaluation showed a 6-cm submucosal mass approximately 10 cm from the dente line projecting as an endoluminal mass with a large broad base. An initial endoscopic resection was attempted but aborted because of significant hemorrhage, and surgical oncology was consulted. After stabilization, the patient underwent a transanal resection of the mass the following day. An endoscopic gastrointestinal anastomosis stapler resulted in a margin-negative complete resection of what was later determined to be a high-grade synovial cell sarcoma. This case report presents the first known documented case of synovial cell sarcoma of the rectum.

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Current Status of MRI and PET in the NCCN Guidelines for Prostate Cancer

Brandon R. Mason, James A. Eastham, Brian J. Davis, Lance A. Mynderse, Thomas J. Pugh, Richard J. Lee, and Joseph E. Ippolito

Prostate cancer (PCa) represents a significant source of morbidity and mortality for men in the United States, with approximately 1 in 9 being diagnosed with PCa in their lifetime. The role of imaging in the evaluation of men with PCa has evolved and currently plays a central role in diagnosis, treatment planning, and evaluation of recurrence. Appropriate use of multiparametric MRI (mpMRI) and MRI-guided transrectal ultrasound (MR-TRUS) biopsy increases the detection of clinically significant PCa while decreasing the detection of clinically insignificant PCa. This process may help patients with clinically insignificant PCa avoid the adverse effects of unnecessary therapy. In the setting of a known PCa, patients with low-grade disease can be observed using active surveillance, which often includes a combination of prostate-specific antigen (PSA) testing, serial mpMRI, and, if indicated, follow-up systematic and targeted TRUS-guided tissue sampling. mpMRI can provide important information in the posttreatment setting, but PET/CT is creating a paradigm shift in imaging standards for patients with locally recurrent and metastatic PCa. This article examines the strengths and limitations of mpMRI for initial PCa diagnosis, active surveillance, recurrent disease evaluation, and image-guided biopsies, and the use of PET/CT imaging in men with recurrent PCa. The goal of this review is to provide a rational basis for current NCCN Clinical Practice Guidelines in Oncology for PCa as they pertain to the use of these advanced imaging modalities.

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Predictors and Temporal Trends of Adjuvant Aromatase Inhibitor Use in Breast Cancer

Tiffany H. Svahn, Joyce C. Niland, Robert W. Carlson, Melissa E. Hughes, Rebecca A. Ottesen, Richard L. Theriault, Stephen B. Edge, Anne F. Schott, Michael A. Bookman, and Jane C. Weeks

After the first report of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial, adjuvant aromatase inhibitor use increased rapidly among National Comprehensive Cancer Network member institutions. Increased aromatase inhibitor use was associated with older age, vascular disease, overexpression of human epidermal growth factor receptor 2 (HER2), or more advanced stage, and substantial variation was seen among institutions. This article examines adjuvant endocrine therapy in postmenopausal women after the first report of the trial, identifies temporal relationships in aromatase inhibitor use, and examines characteristics associated with choice of endocrine therapy among 4044 postmenopausal patients with hormone receptor–positive nonmetastatic breast cancer presenting from July 1997 to December 2004. Multivariable logistic regression analysis examined temporal associations and characteristics associated with aromatase inhibitor use. Time-trend analysis showed increased aromatase inhibitor and decreased tamoxifen use after release of ATAC results (P < .0001). In multivariable regression analysis, institution (P <. 0001), vascular disease (P <. 0001), age (P = .0002), stage (P = .0002), and HER2 status (P = .0009) independently predicted aromatase inhibitor use. Institutional rates of use ranged from 15% to 66%. Adjuvant aromatase inhibitor use increased after the first report of ATAC, with this increase associated with older age, vascular disease, overexpression of HER2, or more advanced stage. Substantial variation was seen among institutions.

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Status of the Clinician Investigator in America: An Essential Healthcare Provider Driving Advances in Cancer Care

Randall F. Holcombe, Claire F. Verschraegen, Andrew E. Chapman, David Gaffney, Richard M. Goldberg, Ruben A. Mesa, Mohammed Milhem, Martha Mims, Edith P. Mitchell, Dan Mulkerin, and Srinivasan Vijayakumar

Background: Translation of basic discoveries to clinical care for patients with cancer is a difficult process greatly enabled by physician-trained researchers. Three categories of physicians, with responsibilities spanning from laboratory and preclinical research to direct patient care, are involved in the translational research continuum: physician-scientist (PS), clinician investigator (CI), and academic clinician (AC). Methods: To define how protected time for research efforts is supported, the Association of American Cancer Institutes (AACI) conducted a survey of their member institutions, obtaining 56 responses documenting time spent in research and clinical activities across multiple cancer disciplines, and providing information about funding streams for the different categories of cancer physicians. Results: Responses showed that PSs and ACs are minimally involved in clinical research activities; the driver or clinical research in academic cancer centers is the CI. A significant concern was a lack of stable funding streams for nonbillable clinical research activities, putting the sustainability of the CI in jeopardy. Limited funding was derived from hospital sources, with most support derived from cancer center sources. Conclusions: This study highlights the importance of the CI in translational cancer medicine and represents a call to action for institutions and research funding agencies to develop new programs targeted toward CI support to ensure continued progress against cancer.

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NCCN Task Force Report: Bone Health and Cancer Care

Richard L. Theriault, J. Sybil Biermann, Elizabeth Brown, Adam Brufsky, Laurence Demers, Ravinder K. Grewal, Theresa Guise, Rebecca Jackson, Kevin McEnery, Donald Podoloff, Peter Ravdin, Charles L. Shapiro, Matthew Smith, and Catherine H. Van Poznak

Higher incidences of osteoporosis and osteopenia are found in cancer patients, particularly in women receiving aromatase inhibitors or with chemotherapy-induced ovarian failure, or in men with prostate cancer and androgen deprivation therapy. Therefore, management of long-term bone health is emerging as an important aspect of comprehensive cancer care. Patients with cancer typically have a number of additional risk factors for osteoporosis that should prompt screening, regardless of patient age or sex. Maintaining bone health requires a broad knowledge base, including understanding underlying bone metabolism and how it is affected by both cancer itself and the drugs used to treat cancer, the effect of chemotherapy-induced menopause on bone health, bone markers and imaging techniques used to assess bone health, therapeutic strategies to maintain bone health, and treatment of bone metastases, including surgery for pathologic fractures. Multiple members of the healthcare team may need to be involved in education and care of the patient. This report summarizes discussion of these and other issues regarding bone health and cancer care from the NCCN Bone Health and Cancer Care Task Force meeting in early 2006. (JNCCN 2006;4(Suppl 2):S1-S24)

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Frequency, Morbidity, and Mortality of Bone Metastases in Advanced Hepatocellular Carcinoma

James J. Harding, Ghaith Abu-Zeinah, Joanne F. Chou, Dwight Hall Owen, Michele Ly, Maeve Aine Lowery, Marinela Capanu, Richard Do, Nancy E. Kemeny, Eileen M. O'Reilly, Leonard B. Saltz, and Ghassan K. Abou-Alfa

Background: Bone metastases are common in hepatocellular carcinoma (HCC), but their incidence, morbidity, and mortality are not well defined. Methods: The Memorial Sloan Kettering Cancer Center database was queried for all patients with HCC and metastases seen from 2002 to 2014. The prevalence of bone metastasis was determined and cumulative incidence function was used to estimate the probability of developing a bone metastasis. Regression models were created to identify risk factors for osseous metastasis. The frequency of skeletal-related events (SREs), defined as pathologic fracture, spinal cord compression, need for radiation therapy to bone, and/or surgical resection of bone, was determined and cumulative incidence function was used to estimate the probability of SRE development. Regression models were created to identify SRE risk factors. Correlation of clinicopathologic parameters, including bone metastases and SREs, with overall survival was analyzed using Kaplan-Meier methodology. Results: A total of 459 patients with HCC and extrahepatic metastases were identified; 151 patients (32.9%) had or developed bone metastases: 128 (27.9%) as a primary site and 23 (4.6%) as a secondary site of extrahepatic disease. Among the 331 patients without bone metastasis at presentation, the yearly incidence of bone metastasis was 6.4% (95% CI, 3.6%–9.2%). Hepatitis B virus (HBV) infection increased the chance of developing a bone metastasis (P=.02). The cumulative incidence of SREs was 50% at 6 months. Univariate analysis showed that patients with HBV-related HCC had a significantly higher incidence of SREs (P=.02). Sorafenib and bisphosphonates each protected against SREs. The presence of SREs was independently associated with a worse overall survival (hazard ratio, 2.13; 95% CI, 1.52–2.97; P<.01) in the multivariable model. Conclusions: Patients with AJCC stage IV HCC and bone metastases that are clinically evident on routine radiography or on clinical examination at presentation are apt to develop frequent, morbid, and mortal SREs, whereas those without evident bone metastasis at presentation are unlikely to develop these complications.

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NCCN Task Force Report: Adjuvant Therapy for Breast Cancer

Robert W. Carlson, Elizabeth Brown, Harold J. Burstein, William J. Gradishar, Clifford A. Hudis, Charles Loprinzi, Eleftherios Paul Mamounas, Edith A. Perez, Kathleen Pritchard, Peter Ravdin, Abram Recht, George Somlo, Richard L. Theriault, Eric P. Winer, Antonio C. Wolff, and for the NCCN Adjuvant Therapy for Breast Cancer Task Force

Abstract

The National Comprehensive Cancer Network (NCCN) first published the NCCN Breast Cancer Treatment Guidelines in 1996. The Guidelines address the treatment of all stages of breast cancer across the spectrum of patient care and have been updated yearly. Adjuvant therapy for breast cancer has undergone an especially rapid evolution over the past few years. Therefore, the NCCN Breast Cancer Guidelines Panel was supplemented by additional experts to form the Adjuvant Therapy Task Force to provide a forum for an extended discussion and expanded input to the adjuvant therapy recommendations for the Breast Cancer Treatment Guidelines. Issues discussed included methods of risk-stratification for recurrence; how biologic markers such as HER2 status, quantitative estrogen receptor, or genetic markers can be incorporated as prognostic or predictive factors; and how age, menopausal status, and estrogen receptor levels impact benefits from chemotherapy and endocrine therapy. Additionally, the task force discussed the strategies for use of aromatase inhibitors in postmenopausal women and the potential incorporation of trastuzumab into adjuvant therapy of women with HER2/neu positive breast cancer. This supplement summarizes the background data and ensuing discussion from the Adjvuant Task Force meeting. (JNCCN 2006;4[suppl 1]:S-1–S-26)

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Are NCI Cancer Centers Providing Adolescents and Young Adults With Cancer Focused Clinical Services? A National Survey

Katherine Daunov, Michael Daunov, Kara Noskoff, Hilary Gan, Simon Davies, Megan Farrell, Whitney Hadley, Amelia Baffa, Jennifer Giesel, Rachel Egler, Alex Y. Huang, John J. Letterio, and Richard T. Lee

Background: This study sought to evaluate the current services and delivery models of adolescent and young adult oncology (AYAO)–specific programs at NCI-designated Cancer Centers (NCI-CCs). Patients and Methods: NCI, academic, and community cancer centers were electronically sent surveys from October to December 2020 and administered via REDCap. Results: Survey responses were received from 50 of 64 (78%) NCI-CCs, primarily completed by pediatric oncologists (53%), adult oncologists (11%), and social workers (11%). Half (51%) reported an existing AYAO program, with most (66%) started within the past 5 years. Although most programs combined medical and pediatric oncology (59%), 24% were embedded within pediatrics alone. Most programs saw patients aged 15 (55%) to 39 years (66%) mainly via outpatient clinic consultation (93%). Most centers reported access to a range of medical oncology and supportive services, but dedicated services specifically for adolescent and young adults (AYAs) were available at a much lower extent, such as social work (98% vs 58%) and psychology (95% vs 54%). Although fertility preservation was offered by all programs (100%), only two-thirds of NCI centers (64%) reported providing sexual health services to AYAs. Most NCI-CCs (98%) were affiliated with a research consortium, and a lesser extent (73%) reported collaboration between adult and pediatric researchers. Nearly two-thirds (60%) reported that AYA oncology care was important/very important to their respective institution and reported providing good/excellent care to AYAs with cancer (59%), but to a lesser extent reported good/excellent research (36%), sexual health (23%), and education of staff (21%). Conclusions: Results of this first-ever national survey to assess AYAO programs showed that only half of NCI-CCs report having a dedicated AYAO program, and that areas of improvement include staff education, research, and sexual health services for patients.