From Theory to Practice: Implementation of Strategies to Reduce Acute Care Visits in Patients With Cancer.

Patients with cancer frequently seek acute care as a result of complications of their disease and adverse effects of treatment. This acute care comes at high cost to the health care system and often results in suboptimal outcomes for patients and their caregivers. The Department of Health and Human Services has identified this as a gap in our care of patients with cancer and has called for quality-improvement efforts to reduce this acute care. We highlight the efforts of three centers-a community practice, an academic practice, and a cancer center-to reduce acute care for their patients. We describe the foundational principles, the practice innovation and implementation strategy, the initial results, and the lessons learned from these interventions. Each of the described interventions sought to integrate evidence-based best practices for reducing unplanned acute care. The first, a telephone triage system, led to 82% of calls being managed at home and only 2% being directed to an emergency department (ED) or hospital. The second, a 24-hour continuity clinic, led to a 26% reduction in ED utilization for patients with cancer. The third, a digital symptom monitoring and management program for high-risk patients on active treatment, led to a 17% reduction in ED presentations. There is a need for innovative care delivery models to improve the management of symptoms for patients with cancer. Future research is needed to determine the elements of these models with the greatest impact and how successful models can be scaled to other institutions.

Mitochondrial and glycolytic metabolic compartmentalization in diffuse large B-cell lymphoma.

Metabolic heterogeneity between neoplastic cells and surrounding stroma has been described in several epithelial malignancies; however, the metabolic phenotypes of neoplastic lymphocytes and neighboring stroma in diffuse large B-cell lymphoma (DLBCL) is unknown. We investigated the metabolic phenotypes of human DLBCL tumors by using immunohistochemical markers of glycolytic and mitochondrial oxidative phosphorylation (OXPHOS) metabolism. The lactate importer MCT4 is a marker of glycolysis, whereas the lactate importer MCT1 and TOMM20 are markers of OXPHOS metabolism. Staining patterns were assessed in 33 DLBCL samples as well as 18 control samples (non-neoplastic lymph nodes). TOMM20 and MCT1 were highly expressed in neoplastic lymphocytes, indicating an OXPHOS phenotype, whereas non-neoplastic lymphocytes in the control samples did not express these markers. Stromal cells in DLBCL samples strongly expressed MCT4, displaying a glycolytic phenotype, a feature not seen in stromal elements of non-neoplastic lymphatic tissue. Furthermore, the differential expression of lactate exporters (MCT4) on tumor-associated stroma and lactate importers (MCT1) on neoplastic lymphocytes support the hypothesis that neoplastic cells are metabolically linked to the stroma likely via mutually beneficial reprogramming. MCT4 is a marker of tumor-associated stroma in neoplastic tissue. Our findings suggest that disruption of neoplastic-stromal cell metabolic heterogeneity including MCT1 and MCT4 blockade should be studied to determine if it could represent a novel treatment target in DLBCL.

Hodgkin lymphoma: A complex metabolic ecosystem with glycolytic reprogramming of the tumor microenvironment.

BACKGROUND: Twenty percent of patients with classical Hodgkin Lymphoma (cHL) have aggressive disease defined as relapsed or refractory disease to initial therapy. At present we cannot identify these patients pre-treatment. The microenvironment is very important in cHL because non-cancer cells constitute the majority of the cells in these tumors. Non-cancer intra-tumoral cells, such as tumor-associated macrophages (TAMs) have been shown to promote tumor growth in cHL via crosstalk with the cancer cells. Metabolic heterogeneity is defined as high mitochondrial metabolism in some tumor cells and glycolysis in others. We hypothesized that there are metabolic differences between cancer cells and non-cancer tumor cells, such as TAMs and tumor-infiltrating lymphocytes in cHL and that greater metabolic differences between cancer cells and TAMs are associated with poor outcomes. METHODS: A case-control study was conducted with 22 tissue samples of cHL at diagnosis from a single institution. The case samples were from 11 patients with aggressive cHL who had relapsed after standard treatment with adriamycin, bleomycin, vinblastine, and dacarbazine (ABVD) or were refractory to this treatment. The control samples were from 11 patients with cHL who achieved a remission and never relapsed after ABVD. Reactive non-cancerous lymph nodes from four subjects served as additional controls. Samples were stained by immunohistochemistry for three metabolic markers: translocase of the outer mitochondrial membrane 20 (TOMM20), monocarboxylate transporter 1 (MCT1), and monocarboxylate transporter 4 (MCT4). TOMM20 is a marker of mitochondrial oxidative phosphorylation (OXPHOS) metabolism. Monocarboxylate transporter 1 (MCT1) is the main importer of lactate into cells and is a marker of OXPHOS. Monocarboxylate transporter 4 (MCT4) is the main lactate exporter out of cells and is a marker of glycolysis. The immunoreactivity for TOMM20, MCT1, and MCT4 was scored based on staining intensity and percentage of positive cells, as follows: 0 for no detectable staining in > 50% of cells; 1+ for faint to moderate staining in > 50% of cells, and 2+ for high or strong staining in > 50% of cells. RESULTS: TOMM20, MCT1, and MCT4 expression was significantly different in Hodgkin and Reed Sternberg (HRS) cells, which are the cancerous cells in cHL compared with TAMs and tumor-associated lymphocytes. HRS have high expression of TOMM20 and MCT1, while TAMs have absent expression of TOMM20 and MCT1 in all but two cases. Tumor-infiltrating lymphocytes have low TOMM20 expression and absent MCT1 expression. Conversely, high MCT4 expression was found in TAMs, but absent in HRS cells in all but one case. Tumor-infiltrating lymphocytes had absent MCT4 expression. Reactive lymph nodes in contrast to cHL tumors had low TOMM20, MCT1, and MCT4 expression in lymphocytes and macrophages. High TOMM20 and MCT1 expression in cancer cells with high MCT4 expression in TAMs is a signature of high metabolic heterogeneity between cancer cells and the tumor microenvironment. A high metabolic heterogeneity signature was associated with relapsed or refractory cHL with a hazard ratio of 5.87 (1.16-29.71; two-sided P < .05) compared with the low metabolic heterogeneity signature. CONCLUSION: Aggressive cHL exhibits features of metabolic heterogeneity with high mitochondrial metabolism in cancer cells and high glycolysis in TAMs, which is not seen in reactive lymph nodes. Future studies will need to confirm the value of these markers as prognostic and predictive biomarkers in clinical practice. Treatment intensity may be tailored in the future to the metabolic profile of the tumor microenvironment and drugs that target metabolic heterogeneity may be valuable in this disease.

Clinical Pathways: Recommendations for Putting Patients at the Center of Value-Based Care.

Two major trends that have been affecting the provision of oncology care in the United States are a shift from volume-based to value-based care and a push toward patient-centered healthcare. However, these two trends are not always completely aligned with each other. Value-based payment models, including clinical pathways, are one strategy being implemented by oncology stakeholders to help encourage the uptake of value-based oncology care. If structured with the patient in mind, they can improve quality of care for patients with cancer, decrease inappropriate care while enabling appropriate personalization of care, and constrain rising prices by demanding a stronger link between cost and value. If not structured appropriately, they can limit patient choice, impede access to innovative treatments, and encourage one-size-fits-all oncology care. Clin Cancer Res; 23(16); 4545-9. ©2017 AACR.

Metformin effects on head and neck squamous carcinoma microenvironment: Window of opportunity trial.

OBJECTIVE: The tumor microenvironment frequently displays abnormal cellular metabolism, which contributes to aggressive behavior. Metformin inhibits mitochondrial oxidative phosphorylation, altering metabolism. Though the mechanism is unclear, epidemiologic studies show an association between metformin use and improved outcomes in head and neck squamous cell carcinoma (HNSCC). We sought to determine if metformin alters metabolism and apoptosis in HNSCC tumors. STUDY DESIGN: Window of opportunity trial of metformin between diagnostic biopsy and resection. Participants were patients with newly diagnosed HNSCC. Fifty patients were enrolled, and 39 completed a full-treatment course. Metformin was titrated to standard diabetic dose (2,000 mg/day) for a course of 9 or more days prior to surgery. METHODS: Immunohistochemistry (IHC) for the metabolic markers caveolin-1 (CAV1), B-galactosidase (GALB), and monocarboxylate transporter 4 (MCT4), as well as the Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) apoptosis assay and Ki-67 IHC, were performed in pre- and postmetformin specimens. Exploratory mass spectroscopy imaging (MSI) to assess lactate levels also was performed in three subjects. RESULTS: Metformin was well tolerated. The average treatment course was 13.6 days. Posttreatment specimens showed a significant increase in stromal CAV1 (P < 0.001) and GALB (P < 0.005), as well as tumor cell apoptosis by TUNEL assay (P < 0.001). There was no significant change in stromal MCT4 expression or proliferation measured by Ki67. Lactate levels in carcinoma cells were increased 2.4-fold postmetformin (P < 0.05), as measured by MSI. CONCLUSION: Metformin increases markers of reduced catabolism and increases senescence in stromal cells as well as carcinoma cell apoptosis. This study demonstrates that metformin modulates metabolism in the HNSCC microenvironment. LEVEL OF EVIDENCE: 4. Laryngoscope, 127:1808-1815, 2017.

Multicompartment metabolism in papillary thyroid cancer.

OBJECTIVES/HYPOTHESIS: In many cancers, varying regions within the tumor are often phenotypically heterogeneous, including their metabolic phenotype. Further, tumor regions can be metabolically compartmentalized, with metabolites transferred between compartments. When present, this metabolic coupling can promote aggressive behavior. Tumor metabolism in papillary thyroid cancer (PTC) is poorly characterized. STUDY DESIGN: Immunohistochemical staining of tissue samples. METHODS: Papillary thyroid cancer specimens from 46 patients with (n = 19) and without advanced disease (n = 27) were compared to noncancerous thyroid tissue (NCT) and benign thyroid specimens (n = 6 follicular adenoma [FA] and n = 5 nodular goiter [NG]). Advanced disease was defined as the presence of lateral neck lymphadenopathy. Immunohistochemistry was performed for translocase of outer mitochondrial membrane 20 (TOMM20), a marker of oxidative phosphorylation, and monocarboxylate transporter 4 (MCT4), a marker of glycolysis. RESULTS: Papillary thyroid cancer and FA thyrocytes had high staining for TOMM20 compared to NCT and nodular goiter (NG) (P < 0.01). High MCT4 staining in fibroblasts was more common in PTC with advanced disease than in any other tissue type studied (P < 0.01). High MCT4 staining was found in all 19 cases of PTC with advanced disease, in 11 of 19 samples with low-stage disease, in one of five samples of FA, in one of 34 NCT, and in 0 of six NG samples. Low fibroblast MCT4 staining in PTC correlated with the absence of clinical adenopathy (P = 0.028); the absence of extrathyroidal extension (P = 0.004); low American Thyroid Association risk (P = 0.001); low AGES (age, grade, extent, size) score (P = 0.004); and low age, metastasis, extent of disease, size risk (P = 0.002). CONCLUSION: This study suggests that multiple metabolic compartments exist in PTC, and low fibroblast MCT4 may be a biomarker of indolent disease. LEVEL OF EVIDENCE: N/A. Laryngoscope, 126:2410-2418, 2016.

Lessons From Early Implementation of a Patient-Centered Care Model in Oncology.

PURPOSE: Oncology practices may serve as the primary health provider for patients with cancer and the so-called neighbor during periods of transition and survivorship. New standards for patient-centered oncology practice articulate expectations for the primary health provider and neighbor roles. We report the implementation experiences of five oncology practices participating in a pilot of these standards. METHODS: For each practice, auditors reviewed workflows and documentation supporting the progress of the practice in meeting the oncology medical home standards. We also observed clinical encounters and practice workflow and interviewed clinicians, staff, and patients. RESULTS: Referral coordination and care management were the most demonstrated functions. The least commonly demonstrated functions related to tracking and coordination of tests and medications, as well as quality measurement and improvement. Some opportunities for structural and process improvement included improving the use of health information technology, care coordination, quality improvement, telephone triage, symptom management, patient education, financial counseling, and care team communication. Making patient-centered care a priority and motivation to change were cited as facilitators for transformation. CONCLUSION: The pilot oncology practices had many structures and processes in common, many of which were established during the early intervention period of this pilot. However, there was little standardization within and across practices in the way these processes were established and documented. Establishing structures for care coordination, quality improvement, and quality measurement should be priorities for practices considering transformation to a patient-centered model of care.

The patient-centered medical home in oncology: from concept to reality.

In recent years, the cost of providing quality cancer care has been subject to an epic escalation causing concerns on the verge of a health care crisis. Innovative patient-management models in oncology based on patient-centered medical home (PCMH) principles, coupled with alternative payments to traditional fee for service (FFS), such as bundled and episodes payment are now showing evidence of effectiveness. These efforts have the potential to bend the cost curve while also improving quality of care and patient satisfaction. However, going forward with FFS alternatives, there are several performance-based payment options with an array of financial risks and rewards. Most novel payment options convey a greater financial risk and accountability on the provider. Therefore, the oncology medical home (OMH) can be a way to mitigate some financial risks by sharing savings with the payer through better global care of the patient, proactively preventing complications, emergency department (ED) visits, and hospitalizations. However, much of the medical home infrastructure that is required to reduced total costs of cancer care comes as an added expense to the provider. As best-of-practice quality standards are being elucidated and refined, we are now at a juncture where payers, providers, policymakers, and other stakeholders should work in concert to expand and implement the OMH framework into the variety of oncology practice environments to better equip them to assimilate into the new payment reform configurations of the future.

Tumor microenvironment in head and neck squamous cell carcinoma.

The tumor microenvironment (TME) of head and neck squamous cell carcinoma (HNSCC) is comprised of cancer-associated fibroblasts (CAFs), immune cells, and other supporting cells. Genetic changes in the carcinoma cells, such as alterations to TP53, NOTCH1, and specific gene expression profiles, contribute to derangements in cancer and microenvironment cells such as increased ROS, overproduction of cytokines, and epithelial to mesenchymal transition (EMT). CAFs are among the most critical elements of the TME contributing to proliferation, invasion, and metastasis. The adaptive immune response is suppressed in HNSCC through overexpression of cytokines, triggered apoptosis of T cells, and alterations in antigen processing machinery. Overexpression of critical cytokines, such as transforming growth factor-ß (TGF-ß), contributes to EMT, immune suppression, and evolution of CAFs. Inflammation and hypoxia are driving forces in angiogenesis and altered metabolism. HNSCC utilizes glycolytic and oxidative metabolism to fuel tumorigenesis via coupled mechanisms between cancer cell regions and cells of the TME. Increased understanding of the TME in HNSCC illustrates that the long-held notion of "condemned mucosa" reflects a process that extends beyond the epithelial cells to the entire tissue comprised of each of these elements.

Understanding and surviving the transition to value-based oncology.

This paper and the three presentations it supports are drawn from the theme of the 2012 Cancer Center Business Summit (CCBS): "Transitioning to Value-Based Oncology: Strategies to Survive and Thrive." The CCBS is a forum on oncology business innovation, and the principal question the organizers address each year is "What are the creative, innovative, and best business models and practices that are being conceived or piloted today that may provide a responsible and sustainable platform for the delivery of cancer care tomorrow?" At this moment in health care-when so much is in flux and new business models and solutions abound-the oncology sector has a solemn responsibility: to forge the business models and relationships that will help to define a new cancer care value proposition and a sustainable health care system of tomorrow for the benefit of the patients it serves to get it "right."

Oncology patient-centered medical home.

The oncology patient-centered medical home is a physician-driven, patient-focused value proposition that can make a difference for patients, oncologists, and the cost of health care.

Defining Value in Cancer Care: AVBCC 2012 Steering Committee Report.

Approximately 200 oncologists, payers, employers, managed care executives, pharmacy benefit managers, and other healthcare stakeholders convened in Houston, TX, on March 28-31, 2012, for the Second Annual Conference of the Association for Value-Based Cancer Care (AVBCC). The mission of the conference was to align the various perspectives around the growing need of defining value in cancer care and developing strategies to enhance patient outcomes. The AVBCC conference presented a forum for the various viewpoints from all the stakeholders across the cancer care continuum, featuring more than 20 sessions and symposia led by nearly 30 oncology leaders. The discussions focused on current trends and challenges in optimizing value in oncology by reducing or controlling cost while improving care quality and patient outcomes, introducing emerging approaches to management and tools that providers and payers are using to enhance cancer care collaboratively. The AVBCC Second Annual Conference was opened by a Steering Committee discussion of 11 panel members who attempted to define value in cancer care and articulated action steps that can help to implement value into cancer care delivery. The following summary represents highlights from the Steering Committee discussion, which was moderated by Gene Beed, MD, and Gary M. Owens, MD.

Barriers to participation in cancer prevention clinical trials.

BACKGROUND: Cancer prevention clinical trials seek to enroll individuals at increased risk for cancer. Little is known about attitudes among physicians and at-risk individuals towards cancer prevention clinical trials. We sought to characterize barriers to prevention trial participation among medical oncologists and first-degree relatives of their patients. METHODS: Physician participants were practicing oncologists in Pennsylvania. Eligible first-degree participants were adult relatives of a cancer patient being treated by one of the study physicians. The influence of perceived psychosocial and practical barriers on level of willingness to participate in cancer prevention clinical trials was investigated. RESULTS: Response rate was low among physicians, 137/478 (29%), and modest among eligible first-degree relatives, 82/129 (64%). Lack of access to an eligible population for prevention clinical trials was the most commonly cited barrier to prevention clinical trials among oncologists. Nearly half (45%) of first-degree relatives had not heard of cancer prevention clinical trials, but 68% expressed interest in learning more, and 55% expressed willingness to participate. In the proportional odds model, greater information source seeking/responsiveness (i.e., interest in learning more about clinical prevention trials from more information sources) (p = 0.04), and having fewer psychosocial barriers (p = 0.02) were associated with a greater willingness to participate. CONCLUSIONS: Many individuals who may be at greater risk for developing cancer because of having a first-degree relative with cancer are unaware of the availability of clinical cancer prevention trials. Nonetheless, many perceive low personal risk associated with these studies, and are interested in learning more.

Barriers to clinical trial participation as perceived by oncologists and patients.

Although clinical trial research is required for the development of improved treatment strategies, very few cancer patients participate in these studies. The purpose of this study was to describe psychosocial barriers to clinical trial participation among oncologists and their cancer patients. A survey was distributed to all medical oncologists in Pennsylvania and a subset of their patients. Relevant background information and assessment of practical and psychosocial barriers to clinical trial participation were assessed. Among 137 oncologists and 170 patients who completed the surveys, 84% of patients were aware of clinical trials, and oncologists and patients generally agreed that clinical trials are important to improving cancer treatment. However, oncologists and patients were more likely to consider clinical trials in advanced or refractory disease. When considering 7 potential barriers to clinical trials, random assignment and fear of receiving a placebo were ranked highly by both patients and oncologists. Patients identified fear of side effects as the greatest barrier to clinical trial participation, whereas oncologists ranked this psychosocial barrier as least important to their patients. Overall, the study found that although oncologists and patients are aware of clinical trials and have favorable attitudes toward them, psychosocial barriers exist for patients that may impact participation in clinical trials. Furthermore, important discrepancies exist between the perceptions of oncologists and those of patients regarding what the psychosocial barriers are. We concluded that characterizing oncologist and patient perceived barriers can help improve communication and decision making about clinical trials, such that participation may be optimized.