Extending venous thromboembolism secondary prevention with apixaban in cancer patients. The EVE trial.

BACKGROUND: Cancer-associated venous thromboembolism (VTE) management guideline recommendations include continued therapeutic anticoagulation while active cancer persists. The Federal Drug Administration label for apixaban for secondary VTE prevention includes a dose reduction to 2.5 mg twice daily after 6 months of treatment. OBJECTIVES: The study's purpose was to determine whether this dose reduction is advisable for cancer-associated VTE. METHODS: A randomized, double-blind trial compared apixaban 2.5 mg with 5 mg twice daily for 12 months among cancer patients with VTE who had completed 6 to 12 months of anticoagulation therapy. The primary outcome was combined major bleeding plus clinically relevant nonmajor bleeding. RESULTS: Of 370 patients recruited, 360 were included in the intention-to-treat analyses. Major plus clinically relevant nonmajor bleeding occurred in 16 of 179 patients (8.9%) in the apixaban 2.5 mg group compared with 22 of 181 patients (12.2%) in the 5 mg group (hazard ratio [HR], 0.72; 95% CI, 0.38-1.37; P = .39). Major bleeding occurred in 2.8% of the apixaban 2.5 mg group and in 2.2% of the 5 mg group (HR, 1.26; 95% CI, 0.34-4.66; P = .73). Recurrent VTE or arterial thrombosis occurred in 9 of 179 patients (5.0%) in the apixaban 2.5 mg group and 9 of 181 patients (5.0%) in the 5 mg group (HR, 1.0; 95% CI, 0.40-2.53; P = 1.00). All-cause mortality rates were similar between groups, 13% vs 12% (HR, 1.14; 95% CI, 0.63-2.04; P = .67). CONCLUSION: For secondary prevention of cancer-associated VTE, apixaban 2.5 mg compared with 5 mg twice daily did not lower combined bleeding events (EVE trial NCT03080883).

Endogenous Heat-Shock Protein Induction with or Without Radiofrequency Ablation or Cryoablation in Patients with Stage IV Melanoma.

LESSONS LEARNED: Percutaneous thermal ablation combined with in situ granulocyte-macrophage colony-stimulating factor cytokine therapy was technically feasible and well tolerated.No significant clinical or immunologic responses were seen. BACKGROUND: Melanoma tumor-derived heat-shock proteins (HSPs) and HSP-peptide complexes can elicit protective antitumor responses. The granulocyte-macrophage colony-stimulating factor (GM-CSF) chemokine can also promote uptake and processing by professional antigen presenting cells (APCs). On this basis, we designed a pilot study of percutaneous thermal ablation as a means to induce heat-shock protein vaccination plus GM-CSF to determine safety and preliminary antitumor activity of this combination. MATERIALS AND METHODS: This study was designed to assess overall safety of percutaneous ablation combined with GM-CSF for unresectable, metastatic melanoma including uveal and mucosal types. All patients received heat-shock therapy (42°C for 30 minutes), then received one of three treatments: (a) intralesional GM-CSF (500 mcg standard dose); (b) radiofrequency ablation (RFA) + GM-CSF; or (c) cryoablation plus GM-CSF. The primary endpoint of the study was the induction of endogenous HSP70 and melanoma-specific cytotoxic T lymphocytes (CTL). RESULTS: Nine patients (three per study arm) were enrolled. No dose-limiting toxicity was observed as specified per protocol. All patients developed progressive disease and went on to receive alternative therapy. Median overall survival (OS) was 8.2 months (95% confidence interval [CI] 2-17.2). The study was not powered to detect a difference in clinical outcome among treatment groups. CONCLUSION: Percutaneous thermal ablation plus GM-CSF was well tolerated, technically feasible, and demonstrated an acceptable adverse event profile comparable to conventional RFA and cryoablation. While HSP70 was induced following therapy, the degree of HSP70 elevation was not associated with clinical outcome or induced CTL responses. While percutaneous thermal ablation plus GM-CSF combinations including checkpoint inhibitors could be considered in future studies, the use of GM-CSF remains experimental and for use in the context of clinical trials.

Tumor status at 12 weeks predicts survival in advanced colorectal cancer: findings from NCCTG N9741.

PURPOSE: We explored the prognostic value of actual tumor measurements (TM) versus World Health Organization (WHO) criteria as three-level (responder, stable, and progression) and two-level (responder and non-responder) variables at 12 and 24 weeks as predictors of survival in Intergroup Trial N9741, a phase III trial in metastatic colorectal cancer (CRC). METHODS: All patients with measurable disease (N = 1,188) were included. The percentage changes in TM from baseline to 12 and 24 weeks were calculated. The prognostic values of TM versus WHO criteria (as three- and two-level variables) at 12 and 24 weeks were compared, using Cox models for overall survival (OS) in a landmark analysis, adjusting for baseline tumor size, performance status, and treatment arm. RESULTS: Tumor status at 12 weeks by WHO criteria (three or two levels) or actual TM were all strongly associated with OS. Actual TM provided no meaningful additional benefit compared with the three-level WHO criteria. Tumor status at 24 weeks was also strongly associated with survival, but added no additional prognostic value compared with the 12-week assessment. At 12 weeks, actual TM improved prognostic characterization of patients with WHO status of response, but provided no additional value in patients with stable disease or progression. CONCLUSIONS: In N9741, the use of actual TM, or following tumor status beyond 12 weeks, did not improve survival prediction compared with a single three-level response assessment at 12 weeks, suggesting that 12-week tumor status could be an appropriate phase II trial endpoint in metastatic CRC.

Osseous metastases: drugs that enhance bone integrity and prevent adverse skeletal events.

More than 400,000 cancer patients in the USA contend with bone metastases on an annual basis. These patients often suffer pain, a decline in quality of life, and a shortened survival. As a result, over the past several years, efforts to enhance bone integrity in patients with osseus metastases have become a major research priority. This review discusses the evolving role of bisphosphonates and their side effects, highlights other pharmacological interventions aimed at enhancing bone integrity, and reviews other pragmatic approaches to prevent worsening pain and fractures, as derived from a single institution case series of patients with problematic rib metastases.

A phase 2 consortium (P2C) trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP) for advanced adenocarcinoma of the pancreas.

3-Aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine) is a novel small molecule inhibitor of ribonucleotide reductase (RR) with clinical signs of activity in pancreatic cancer. Therefore, the Phase 2 Consortium (P2C) initiated a trial (two single stage studies with planned interim analysis) of 3-AP at 96 mg/m(2) intravenously days 1-4 and 15-18 of a 28-day cycle in both chemotherapy-naive and gemcitabine-refractory (GR) patients with advanced pancreatic cancer. The primary endpoint was survival at six months (chemotherapy-naive) and four months (GR). Secondary endpoints were toxicity, response, overall survival, time to progression and mechanistic studies. Fifteen patients were enrolled including one chemotherapy-naïve and 14 GR. The chemotherapy-naïve patient progressed during cycle 1 with grade 3 and 4 toxicities. Of 14 GR patients, seven received two cycles, six received one cycle and one received eight cycles. Progression precluded further treatment in 11 GR patients. Additionally, one died of an ileus in cycle 1 considered related to treatment and two stopped treatment due to toxicity. Five GR patients had grade 4 toxicities possibly related to 3-AP and six GR patients had grade 3 fatigue. Toxicities and lack of meaningful clinical benefit prompted early study closure. Four-month survival in GR patients was 21% (95% CI: 8-58%). Correlative studies confirmed that 3-AP increased the percentage of S-phase buccal mucosal cells, the presence of multidrug resistance gene polymorphisms appeared to predict leukopenia, and baseline pancreatic tumor RR M2 expression was low relative to other tumors treated with 3-AP. In conclusion, this regimen appears inactive against predominantly GR pancreatic cancer. RR M2 protein may not have a critical role in the malignant potential of pancreatic cancer.

Treatment with panitumumab after a severe infusion reaction to cetuximab in a patient with metastatic colorectal cancer: a case report.

Monoclonal antibodies targeting the epidermal growth factor receptor (EGFR) are effective in the treatment of metastatic colorectal cancer. Cetuximab is a human-murine chimeric monoclonal antibody targeting the EGFR. Even with premedication, cetuximab can result in an infusion reaction in select patients. In a portion of these patients, the reaction is severe, and further therapy with cetuximab is contraindicated, thus preventing these patients from receiving potentially beneficial anti-EGFR therapy. Panitumumab is a fully human monoclonal antibody also targeting the EGFR. Panitumumab is given without premedication and, in clinical trials, has rarely been associated with infusion reactions. It is not yet known whether panitumumab can be safely given in patients with a previous severe reaction to cetuximab. We report a case of a patient successfully treated with panitumumab after the patient had a severe infusion reaction to cetuximab.

Verapamil toxicity resulting from a probable interaction with telithromycin.

OBJECTIVE: To report a case of hypotension and bradyarrhythmia caused by verapamil toxicity in a patient prescribed telithromycin. CASE SUMMARY: A 76-year-old white woman receiving verapamil 180 mg/day for hypertension experienced a sudden onset of shortness of breath and weakness and was found to be profoundly hypotensive and bradycardic, with a systolic blood pressure of 50-60 mm Hg and a heart rate of 30 beats/min. She had been taking telithromycin 800 mg/day for 2 days previously for acute sinusitis. The patient was treated with crystalloids, vasopressors, and transvenous pacing. Approximately 72 hours after admission, her blood pressure and heart rate rapidly returned to normal, and she was discharged several days later. DISCUSSION: Telithromycin is a known substrate of the CYP3A4 system, and several pharmacokinetic interactions can occur by displacement of other drugs from this system. Verapamil is metabolized through several cytochrome P450 isoenzyme systems. Although there are no previous reports of an interaction between these drugs, other possible causes for the patient's symptoms were excluded and the diagnosis of a probable interaction between verapamil and telithromycin leading to verapamil toxicity was made. CONCLUSIONS: Telithromycin is a ketolide antibiotic approved for treatment of respiratory tract infections and acute sinusitis. The potential for clinically significant drug interactions should be considered before using this agent, especially in patients taking other drugs that are metabolized through the CYP3A system. Caution should be exercised when considering the use of this antibiotic in patients receiving verapamil.