Oral mucosal injury caused by mammalian target of rapamycin inhibitors: emerging perspectives on pathobiology and impact on clinical practice.

In recent years oral mucosal injury has been increasingly recognized as an important toxicity associated with mammalian target of rapamycin (mTOR) inhibitors, including in patients with breast cancer who are receiving everolimus. This review addresses the state-of-the-science regarding mTOR inhibitor-associated stomatitis (mIAS), and delineates its clinical characteristics and management. Given the clinically impactful pain associated with mIAS, this review also specifically highlights new research focusing on the study of the molecular basis of pain. The incidence of mIAS varies widely (2-78%). As reported across multiple mTOR inhibitor clinical trials, grade 3/4 toxicity occurs in up to 9% of patients. Managing mTOR-associated oral lesions with topical oral, intralesional, and/or systemic steroids can be beneficial, in contrast to the lack of evidence supporting steroid treatment of oral mucositis caused by high-dose chemotherapy or radiation. However, steroid management is not uniformly efficacious in all patients receiving mTOR inhibitors. Furthermore, technology does not presently exist to permit clinicians to predict a priori which of their patients will develop these lesions. There thus remains a strategic need to define the pathobiology of mIAS, the molecular basis of pain, and risk prediction relative to development of the clinical lesion. This knowledge could lead to novel future interventions designed to more effectively prevent mIAS and improve pain management if clinically significant mIAS lesions develop.

Patient, Caregiver, and Nurse Preferences for Treatments for Bone Metastases from Solid Tumors.

BACKGROUND: Bone-targeted agents (BTAs) used for the prevention of skeletal-related events (SREs) associated with metastatic bone disease possess different attributes that factor into treatment decisions. OBJECTIVE: The aim of this study was to evaluate preferences of patients, caregivers, and nurses for features of BTAs used to prevent SREs in patients with a self-reported physician diagnosis of bone metastasis from solid tumors. METHODS: Patients (n = 187), primary caregivers (n = 197), or nurses (n = 196) completed a web-enabled discrete-choice experiment (10-question survey) in which they chose between pairs of hypothetical profiles of BTAs. Each profile was defined by six key treatment attributes, including efficacy and safety (two each) and route/frequency of administration and cost (one each). The relative importance of treatment attributes and levels was estimated. RESULTS: The most important treatment attribute for patients and nurses was out-of-pocket cost, and for caregivers, treatment-related risk of renal impairment. Risk of renal impairment was the second most important attribute for patients and nurses, while time until first SRE was the third most important attribute for all respondents. For nurses, risk of osteonecrosis of the jaw was least important, and for patients and caregivers, mode of administration was least important. LIMITATIONS: Respondents considered hypothetical medications; therefore, their decisions may not have the same consequences as actual decisions. CONCLUSIONS: The perspectives of patients, caregivers, and nurses are integral when making treatment decisions about BTAs to prevent SREs associated with solid tumors. Identifying the relative importance of attributes of BTAs will aid in the proper selection of therapy in this setting, which may improve patient outcomes.

Clinical efficacy of denosumab versus bisphosphonates for the prevention of bone complications: implications for nursing.

Antiresorptive therapies are used for the prevention of skeletal-related events (SREs) associated with metastatic bone disease related to breast cancer, prostate cancer, and other solid tumors. This review highlights the central role of nurses in supporting and educating advanced cancer patients regarding the consequences of bone metastases and SREs, including therapy management options. Contemporary clinical journals reporting evidence-based studies were reviewed. SREs associated with bone metastases can significantly impact the quality of life of advanced cancer patients. Denosumab therapy, an advancement in antiresorptive treatments, significantly prevents and delays the time to develop SREs. In the multifaceted approach required for successful and consistent management of SREs associated with bone metastases, antiresorptive therapies can play a central role in maintaining the functional independence of patients through the prevention of debilitating SREs, thereby preserving quality of life.

Elevation in inflammatory serum biomarkers predicts response to trastuzumab-containing therapy.

Approximately half of all HER2/neu-overexpressing breast cancer patients do not respond to trastuzumab-containing therapy. Therefore, there remains an urgent and unmet clinical need for the development of predictive biomarkers for trastuzumab response. Recently, several lines of evidence have demonstrated that the inflammatory tumor microenvironment is a major contributor to therapy resistance in breast cancer. In order to explore the predictive value of inflammation in breast cancer patients, we measured the inflammatory biomarkers serum ferritin and C-reactive protein (CRP) in 66 patients immediately before undergoing trastuzumab-containing therapy and evaluated their progression-free and overall survival. The elevation in pre-treatment serum ferritin (>250 ng/ml) or CRP (>7.25 mg/l) was a significant predictor of reduced progression-free survival and shorter overall survival. When patients were stratified based on their serum ferritin and CRP levels, patients with elevation in both inflammatory biomarkers had a markedly poorer response to trastuzumab-containing therapy. Therefore, the elevation in inflammatory serum biomarkers may reflect a pathological state that decreases the clinical efficacy of this therapy. Anti-inflammatory drugs and life-style changes to decrease inflammation in cancer patients should be explored as possible strategies to sensitize patients to anti-cancer therapeutics.

Phase II trial of gemcitabine, irinotecan, and celecoxib in patients with advanced pancreatic cancer.

GOALS AND BACKGROUND: Cyclooxygenase-2 (COX-2) has been shown to be expressed in a variety of tumors including pancreatic cancer. The combination of gemcitabine and irinotecan is active in pancreatic cancer. The purpose of this study is to determine the toxicity and response rate to the addition of the selective oral COX-2 inhibitor, celecoxib, to gemcitabine and irinotecan in patients with inoperable pancreatic cancer. STUDY: Twenty-one patients with previously untreated inoperable pancreatic cancer were entered on this trial. Seven patients had localized disease, 8 had metastatic disease, and 6 patients were inevaluable. RESULTS: Twenty percent of the patients had a partial response and 80% of the patients had a stable response with a median response rate of 9 months. The median overall survival was 18 months with 80% of the patients achieving 1-year survival and 20% achieving 2-year survival. Using the FACT-PA scale to measure the quality of life (QOL), 13 of the 15 patients reported an improvement in their QOL and 2 patients reported no change. The median CA19-9 levels for the 13 patients with measurable CA19-9 values, decreased by 71% by cycle 2. Adverse events were acceptable and included neutropenia, thrombocytopenia, nausea, fatigue, and anemia. CONCLUSIONS: The combination of gemcitabine, irinotecan, and celecoxib is an active therapy for inoperable pancreatic cancer. A marked reduction in CA19-9 is observed in all evaluable patients by cycle 2. Toxicity is tolerable and a majority of patients reported a decrease in pain and a significant improvement in their QOL.

Phase I trial of zoledronic acid + imatinib mesylate (Gleevec) in patients with bone metastases.

OBJECTIVES AND METHODS: Patients with bone metastases suffer from long-term skeletal morbidity and a reduction in quality of life. Treatment consists of radiation or surgery to prevent or repair fractures and bisphosphonates to delay skeletal-related events (SRE). Platelet-derived growth factor released from metastatic cancer cells may influence the development and progression of bone metastases. Imatinib mesylate (Gleevec) inhibits platelet-derived growth factor-receptor tyrosine kinase signaling, increases apoptosis, reduces proliferation, and lowers microvessel density in human tumors. This phase I study assessed the effects of the combination of zoledronic acid (a bisphosphonate used to delay SRE) and Gleevec on 15 evaluable patients with osteolytic or osteoblastic bone metastases. RESULTS: Although 6 of 9 patients noted an improvement in pain and 1 patient was stable, the quality of life improved in only 3 patients. Dose limiting toxicity was observed in 0 of 5 (400 mg Gleevec), 2 of 5 (600 mg), and 4 of 5 (800 mg) patients. Although no patient required radiation and only 2 SRE occurred during the study, disease progression in bone and/or extraskeletal sites occurred in most patients. CONCLUSION: The combination of zoledronic acid + Gleevec is not recommended in patients with bone metastases because of toxicity and limited clinical efficacy.