Stephen S. Grubbs

Eliminating Racial Disparities in Colorectal Cancer in the Real World: It Took a Village

Colorectal cancer (CRC) is the third most common cancer in the United States, with more than 102,000 new patients diagnosed per year.1 It is, however, one of the few cancers that is highly preventable through the use of routine screening,2 which can also prevent death resulting from CRC.3,4 CRC is also one cancer that continues to demonstrate widening incidence and survival disparities between whites and African Americans.1,5 Although the reasons for these disparities are multifactorial, advanced stage at diagnosis may explain up to 50% of the survival disparity.6

Effect of longer-interval vs standard dosing of zoledronic acid on skeletal events in patients with bone metastases: A randomized clinical trial

Importance Zoledronic acid, a third-generation aminobisphosphonate, reduces the incidence of skeletal-related events and pain in patients with bone metastases. The optimal dosing interval for zoledronic acid is uncertain. Objective To determine whether zoledronic acid administered every 12 weeks is noninferior to zoledronic acid administered every 4 weeks. Design, Setting, Participants Randomized, open-label clinical trial conducted at 269 academic and community sites in the United States. Patients (n = 1822) with metastatic breast cancer, metastatic prostate cancer, or multiple myeloma who had at least 1 site of bone involvement were enrolled between May 2009 and April 2012; follow-up concluded in April 2014. Interventions Patients were randomized to receive zoledronic acid administered intravenously every 4 weeks (n = 911) vs every 12 weeks (n = 911) for 2 years. Main Outcomes and Measures The primary end point was the proportion of patients having at least 1 skeletal-related event (defined as clinical fracture, spinal cord compression, radiation to bone, or surgery involving bone) within 2 years after randomization and a between-group absolute difference of 7% as the noninferiority margin. Secondary end points included the proportion of patients with at least 1 skeletal-related event by disease type, pain as assessed by the Brief Pain Inventory (range, 0-10; higher scores indicate worse pain), Eastern Cooperative Oncology Group performance status (range, 0-4; higher scores indicate worse disability), incidence of osteonecrosis of the jaw, kidney dysfunction, skeletal morbidity rate (mean number of skeletal-related events per year), and, in a subset of 553 patients, suppression of bone turnover (assessed by C-terminal telopeptide levels). Results Among 1822 patients who were randomized (median age, 65 years; 980 [53.8%] women; 855 with breast cancer, 689 with prostate cancer, and 278 with multiple myeloma), 795 completed the study at 2 years. A total of 260 patients (29.5%) in the zoledronic acid every 4-week dosing group and 253 patients (28.6%) in the every 12-week dosing group experienced at least 1 skeletal-related event within 2 years of randomization (risk difference of −0.3% [1-sided 95% CI, −4% to ∞]; P < .001 for noninferiority). The proportions of skeletal-related events did not differ significantly between the every 4-week dosing group vs the every 12-week dosing group for patients with breast cancer, prostate cancer, or multiple myeloma. Pain scores, performance status scores, incidence of jaw osteonecrosis, and kidney dysfunction did not differ significantly between the treatment groups. Skeletal morbidity rates were numerically identical in both groups, but bone turnover was greater (C-terminal telopeptide levels were higher) among patients who received zoledronic acid every 12 weeks. Conclusions and Relevance Among patients with bone metastases due to breast cancer, prostate cancer, or multiple myeloma, the use of zoledronic acid every 12 weeks compared with the standard dosing interval of every 4 weeks did not result in an increased risk of skeletal events over 2 years. This longer interval may be an acceptable treatment option. Trial Registration clinicaltrials.gov Identifier: NCT00869206

Applying a Conceptual Model for Examining Health-Related Quality of Life in Long-Term Breast Cancer Survivors: CALGB Study 79804

Objectives: The Survivors Health and Reaction study used a quality‐of‐life model adapted for cancer survivors by Dow and colleagues to identify factors related to global health‐related quality of life (HRQL) and to document the prevalence of problems and health‐oriented behaviors in a follow‐up study of breast cancer patients who participated in CALGB 8541.

Clinical Trial Investigator Status: You Need to Earn It

The clinical trials that are conducted by the National Cancer Institute (NCI) represent the core of the clinical program of the NCI’s Center for Cancer Research. At the Center for Cancer Research, clinical and basic science are integrated with the goal of reducing the burden of cancer through discovery, exploration, and bench-tobedside translational treatment and prevention modalities. The goal of the NCI clinical trials program is to answer questions about particular cancers and to identify new therapeutic and prevention interventions, which are performed across the United States at centers participating in NCI-supported research. Sadly, only 2% to 7% of adult patients with cancer across the United States participate in these clinical trials. To make matters worse, the following populations are under-represented among participants in NCI-funded clinical trials: Latinos/Hispanics, Asian and Pacific Islanders, African American men, American Indians/Alaskan Natives, adolescents, older adults (age 65 years), individuals who reside in rural areas, and individuals of low socioeconomic status. The lack of diversity in clinical trials populations reduces the opportunity for discovering effects that may be relevant to a particular under-represented population. The literature has focused on barriers to participation in clinical trials—including both physician and patient issues—such as cost, lack of support personnel, limited access to clinical trials, and the distance that patients may live from centers that participate in NCI clinical trials. In a study by Meropol et al, cognitive, affective, and practical barriers to participation in clinical treatment trials were characterized among Pennsylvania oncologists. Eligible physician participants were practicing medical oncologists in Pennsylvania, and eligible patients were adults at least 18 years of age with cancer undergoing follow-up by medical oncologists in Pennsylvania. Of 137 oncologists and 170 patients who completed the surveys, of patients, 84% were aware of clinical trials, and both oncologists and patients generally agreed that clinical trials were important to improve cancer treatment. It was interesting that oncologists and patients in this report were more likely to consider clinical trials in advanced or refractory disease. When considering seven potential barriers to clinical trials, random assignment and fear of receiving a placebo were highly ranked by both patients and oncologists. Patients identified fear of adverse effects as the greatest barrier to clinical trial participation, whereas oncologists ranked this psychosocial barrier as of least importance to their patients. Although the study found that oncologists and patients in Pennsylvania were aware of clinical trials and had favorable attitudes toward them in principle, psychosocial barriers existed for patients that more than likely reduced participation. One of the key issues in this study was the fact that the oncologists who were surveyed had favorable attitudes toward clinical trials. Surely, there must be oncologists who don’t have favorable attitudes toward clinical trials and are not advocates of clinical trials. This is reflected in the fact that 30% of oncologists are responsible for 70% of the accrual to NCI clinical trials. Although some important pragmatic issues, such as fiscal and administrative support, may affect participation, these are issues that affect all oncologists to varying degrees, yet some oncologists are more successful than others in accruing patients to clinical trials. As reported by the Coalition of Cooperative Groups, community-based practices are responsible for 64% of adult patients accrued in cooperative group–sponsored clinical trials. Academic centers are responsible for 34%, whereas military/Veteran’s Administration hospitals contribute the remaining 2%. Hence, the NCI Community Clinical Oncology Programs (CCOPs) play a major role in adult recruitment to NCI-sponsored clinical trials. Created in 1983 by the National Cancer Institute, the CCOP network allows patients and physicians to participate in state-of-the-art clinical trials for cancer prevention and treatment in their local communities. There are 50 CCOPs and 13 minority-based CCOPs currently funded in 35 states across the United States, the District of Columbia, and Puerto Rico. The Delaware Christiana CCOP was initially funded in 1987. After a restructuring of the cancer program at the Helen F. Graham Cancer Center at Christiana Care in 2001, accrual to NCI clinical trials increased from 9.9% in 2001% to 20% in 2006. There are many reasons for this dramatic increase in clinical trial accrual over a 5-year period, which represents six times the national average. All the reasons for this increase in patient accrual to NCI clinical trials are beyond the content of this article. Briefly, however, this increase has been partly due to the establishment of multidisciplinary disease site centers, placing clinical research nurses in the private practice offices, with a continuous marketing campaign. Nevertheless, despite the improvement of this clinical trials accrual, there is a core of physicians participating in the cancer program whose track record to clinical trial accrual can best be described as dismal. This is despite the fact that there are more than 110 clinical trials available for their patients covering every disease site, with personnel support to help in the recruitment to clinical trials. These individuals are designated members of the NCI Cooperative Groups and many have membership in cooperative groups on their curriculum vitaes. Some investigators have suggested that access to clinical trials should be an objective and a component of state-of-the-art cancer JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 26 NUMBER 15 MAY 2

Health‐related quality of life in long‐term breast cancer survivors

The Survivors Health and Reaction (SHARE) study examined health‐related quality of life (HRQL) in breast cancer patients who had participated in Cancer and Leukemia Group B Trial 8541 from 1985 to 1991.

Glucocorticoids suppress renal cell carcinoma progression by enhancing Na,K-ATPase beta-1 subunit expression.

Glucocorticoids are commonly used as palliative or chemotherapeutic clinical agents for treatment of a variety of cancers. Although steroid treatment is beneficial, the mechanisms by which steroids improve outcome in cancer patients are not well understood. Na,K-ATPase beta-subunit isoform 1 (NaK-β1) is a cell-cell adhesion molecule, and its expression is down-regulated in cancer cells undergoing epithelial-to mesenchymal-transition (EMT), a key event associated with cancer progression to metastatic disease. In this study, we performed high-throughput screening to identify small molecules that could up-regulate NaK-β1 expression in cancer cells. Compounds related to the glucocorticoids were identified as drug candidates enhancing NaK-β1 expression. Of these compounds, triamcinolone, dexamethasone, and fluorometholone were validated to increase NaK-β1 expression at the cell surface, enhance cell-cell adhesion, attenuate motility and invasiveness and induce mesenchymal to epithelial like transition of renal cell carcinoma (RCC) cells in vitro. Treatment of NaK-β1 knockdown cells with these drug candidates confirmed that these compounds mediate their effects through up-regulating NaK-β1. Furthermore, we demonstrated that these compounds attenuate tumor growth in subcutaneous RCC xenografts and reduce local invasiveness in orthotopically-implanted tumors. Our results strongly indicate that the addition of glucocorticoids in the treatment of RCC may improve outcome for RCC patients by augmenting NaK-β1 cell-cell adhesion function.

Cost-Effectiveness Analysis of Monthly Zoledronic Acid, Zoledronic Acid Every 3 Months, and Monthly Denosumab in Women With Breast Cancer and Skeletal Metastases: CALGB 70604 (Alliance)

Purpose Skeletal-related events (SREs) such as pathologic fracture, spinal cord compression, or the necessity for radiation or surgery to bone metastasis cause considerable morbidity, decrements in quality of life, and costs to the health care system. The results of a recent large randomized trial (Cancer and Leukemia Group B/Alliance for Clinical Trials in Oncology [CALGB/Alliance 70604]) showed that zoledronic acid (ZA) every 3 months was noninferior to monthly ZA in reducing the risks of SREs. We sought to determine the cost-effectiveness (CE) of monthly ZA, ZA every 3 months, and monthly denosumab in women with breast cancer and skeletal metastases. Methods Using a Markov model, costs per SRE avoided were calculated for the three treatments. Sensitivity analyses were performed where denosumab SRE probabilities were assumed to be 50%, 75%, and 90% lower than the ZA SRE probabilities. Quality-adjusted life-years were also calculated. The analysis was from the US payer perspective. Results The mean costs of the denosumab treatment strategy are nine-fold higher than generic ZA every 3 months. Quality-adjusted life-years were virtually identical in all the three treatment arms; hence, the optimal treatment would be ZA every 3 months because it was the least costly treatment. The sensitivity analyses showed that relative to ZA every 3 months, the incremental costs per mean SRE avoided for denosumab ranged from

Phase II study of carboplatin, pemetrexed, and bevacizumab in advanced nonsquamous non–small‐cell lung cancer

162,918 to

ReCAP: Clinical Trial Assessment of Infrastructure Matrix Tool to Improve the Quality of Research Conduct in the Community

347,655. Conclusion ZA every 3 months was more CE in reducing the risks of SRE than monthly denosumab. This analysis was one of the first to incorporate the costs of generic ZA and one of the first independent CE analyses not sponsored by either Novartis or Amgen, the makers of ZA and denosumab, respectively. ZA every 3 months is the more CE option and more reasonable alternative to monthly denosumab.

Therapeutic Approaches to Metastatic Bone Cancer II: Targeted and Non-targeted Systemic Agents

Lung cancer remains the leading cause of cancer death throughout the world. Despite new chemotherapeutic, immunomodulating and molecularly targeted agents, patients with locally advanced or metastatic disease still have a poor prognosis. This trial looked to combine antiangiogenic therapy with a first‐line cytotoxic chemotherapy doublet, hoping to extend median progression‐free survival (PFS) while minimizing toxicity in patients with advanced nonsquamous non–small‐cell lung cancer (NSCLC). In this single institution, single‐arm study, 51 patients (age >18 yo) were followed from 2007 to 2012. Patients with stage IV nonsquamous NSCLC and patients with recurrent unresectable disease (nonradiation candidates) were eligible. Treatment consisted of carboplatin AUC 5 IV 30‐60 minutes, pemetrexed 500/mg2 IV 10 minutes, bevacizumab 15 mg/kg IV (90 minutes 1st dose, 60 minutes 2nd dose, 30 minutes subsequent doses). Treatment was administered every 21 days and planned for 6 cycles, in the absence of disease progression or unacceptable toxicities. Growth factor support was not permitted prophylactically but allowed for toxicities, as were dose reductions. Maintenance treatment for those with stable disease or better consisted of Bevacizumab 15 mg/kg every 3 weeks for up to 1 year. Between November 2007 and March 2012, 51 patients were followed in the phase II trial of carboplatin, pemetrexed, and bevacizumab. Patients were enrolled over a 24‐month period. After the end of treatment visits, subjects were followed at least every 3 months for survival data. The median follow‐up period was 49 weeks (6 weeks to 178), and the median number of treatment cycles was 6 (range, 1‐6). Among the 50 patients assessable for response, median overall survival was 49 weeks (95% CI, 0‐62.7) with median PFS of 28 weeks (95% CI, 0‐132.4). A complete or partial response was seen in 28 (59.5%) patients. Grade 3‐4 treatment‐related adverse events occurred in 9 (17.6%) of 51 patients; the most common were thrombocytopenia (4 [7.8%]) and neutropenia (3 [5.9%]). Three (5.8%) of 51 patients were discontinued because of treatment‐related adverse events (grade 3 diarrhea, thrombocytopenia, dehydration, fatigue, and grade 4 respiratory distress), and 1 patient (1.9%) was found to be ineligible due to anticoagulation use. A novel 3‐drug combination for advanced nonsquamous NSCLC shows promising efficacy with modest toxicity.