Evaluation of pharmacokinetics and safety of cetuximab with cisplatin/carboplatin in patients with advanced solid tumor: Result from phase II studies.

The pharmacokinetics and potential drug-drug interactions between cetuximab and cisplatin or carboplatin from two studies (JXBA and JXBB) were evaluated. These studies were multicenter, open-label phase II trials designed to evaluate the drug-drug interactions between cetuximab (400 mg m-2 initial dose) and cisplatin (JXBA; 100 mg m-2) or carboplatin (JXBB; area under the curve [AUC] = 5 mg × min mL-1) with or without 5-fluorouracil (5FU) in patients with advanced solid tumors. Concentrations of cetuximab, cisplatin and carboplatin were determined using analytical methods. The safety and tolerability of cetuximab in combination with cisplatin or carboplatin was also determined in all treated patients. The JXBA study showed that cetuximab serum concentrations were similar when cetuximab was administered alone or in combination with cisplatin. The Cmax, tmax and overall AUC for the cetuximab group (194 µg mL-1, 2.0 hour, 14 900 µg × h mL-1) and the cetuximab and cisplatin combination group (192 µg mL-1, 1.99 hour, 16 300 µg × h mL-1) were similar. The JXBB study showed that mean cetuximab serum concentrations were similar when cetuximab was administered alone or in combination with carboplatin. The Cmax, tmax and overall AUC for the cetuximab group (199 µg mL-1, 1.15 hour, 17 200 µg × h mL-1) and the cetuximab and carboplatin combination group (199 µg mL-1, 3.17 h, 16 800 µg × h mL-1) were similar. Both studies showed that the safety profile was consistent with known side effects of cetuximab, platinum-based therapies and 5-FU. There was no clinically relevant change in cetuximab pharmacokinetics when it was administered in combination with cisplatin or carboplatin.

Vaccination with poly(IC:LC) and peptide-pulsed autologous dendritic cells in patients with pancreatic cancer.

BACKGROUND: Dendritic cells (DCs) enhance the quality of anti-tumor immune response in patients with cancer. Thus, we posit that DC-based immunotherapy, in conjunction with toll-like receptor (TLR)-3 agonist poly-ICLC, is a promising approach for harnessing immunity against metastatic or locally advanced unresectable pancreatic cancer (PC). METHODS: We generated autologous DCs from the peripheral blood of HLA-A2+ patients with PC. DCs were pulsed with three distinct A2-restricted peptides: 1) human telomerase reverse transcriptase (hTERT, TERT572Y), 2) carcinoembryonic antigen (CEA; Cap1-6D), and 3) survivin (SRV.A2). Patients received four intradermal injections of 1 × 107 peptide-pulsed DC vaccines every 2 weeks (Day 0, 14, 28, and 42). Concurrently, patients received intramuscular administration of Poly-ICLC at 30 µg/Kg on vaccination days (i.e., day 0, 14, 28, and 42), as well as on days 3, 17, 21, 31, 37, and 45. Our key objective was to assess safety and feasibility. The effect of DC vaccination on immune response was measured at each DC injection time point by enumerating the phenotype and function of patient T cells. RESULTS: Twelve patients underwent apheresis: nine patients with metastatic disease, and three patients with locally advanced unresectable disease. Vaccines were successfully manufactured from all individuals. We found that this treatment was well-tolerated, with the most common symptoms being fatigue and/or self-limiting flu-like symptoms. Among the eight patients who underwent imaging on day 56, four patients experienced stable disease while four patients had disease progression. The median overall survival was 7.7 months. One patient survived for 28 months post leukapheresis. MHC class I -tetramer analysis before and after vaccination revealed effective generation of antigen-specific T cells in three patients with stable disease. CONCLUSION: Vaccination with peptide-pulsed DCs in combination with poly-ICLC is safe and induces a measurable tumor specific T cell population in patients with advanced PC. TRIAL REGISTRATION: NCT01410968 ; Name of registry: clinicaltrials.gov; Date of registration: 08/04/2011).

Cetuximab and Radiotherapy in Laryngeal Preservation for Cancers of the Larynx and Hypopharynx: A Secondary Analysis of a Randomized Clinical Trial.

IMPORTANCE: The appropriate use of surgery or radiotherapy-based approaches for organ preservation has been the subject of much debate. Unfortunately, there has been a lack of improvement in overall survival for patients with laryngeal carcinoma in the last 30 years. OBJECTIVE: To assess the rates of laryngeal preservation and laryngectomy-free survival in patients receiving cetuximab and radiotherapy (CRT) and patients receiving radiotherapy alone. DESIGN, SETTING, AND PARTICIPANTS: Patients were enrolled in a multicenter, open-label, stratified, randomized, phase 3 study from April 1, 1999, through March 31, 2002, from 73 centers in the United States and 14 other countries. A secondary subgroup analysis of patients with hypopharyngeal and laryngeal carcinoma was undertaken. Rates of laryngeal preservation and laryngectomy-free survival were estimated by the Kaplan-Meier method. The hazard ratios (HRs) were calculated using a Cox proportional hazards regression model. Quality of life was evaluated using the European Organization for Research and Treatment of Cancer core questionnaire and head and neck module. MAIN OUTCOMES AND MEASURES: Laryngeal preservation and laryngectomy-free survival. RESULTS: Of the 424 patients included in the trial, 168 treated patients with cancer of the larynx or hypopharynx were included in this analysis (90 in the CRT group and 78 in the radiotherapy alone group). The median (range) age of the patients was 59 (40-80) years in the CRT group and 61 (35-81) years in the radiotherapy alone group. In the CRT group, 72 patients (80.0%) were male and 18 (20.0%) were female. In the radiotherapy alone group, 62 (79.5%) were male and 16 (20.5%) were female. The rates of laryngeal preservation at 2 years were 87.9% for CRT vs 85.7% for radiotherapy alone, with an HR of 0.57 (95% CI, 0.23-1.42; P = .22). Similarly, the HR for laryngectomy-free survival comparing CRT vs radiotherapy alone was 0.78 (95% CI, 0.54-1.11; P = .17). This study was not powered to assess organ preservation. Median overall survival was 27 (95% CI, 20-45) vs 21 (95% CI, 17-35) months for the CRT and radiotherapy alone groups, respectively, with an HR of 0.87 (95% CI, 0.60-1.27). No differences between treatments were reported regarding overall quality of life, need for a feeding tube, or speech. CONCLUSIONS AND RELEVANCE: The results of a possible cetuximab-related laryngeal preservation benefit for patients with hypopharyngeal or laryngeal cancer are intriguing; these results need to be interpreted in the context of a retrospective subset analysis with limited sample size. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00004227.

Cetuximab plus platinum-based chemotherapy in head and neck squamous cell carcinoma: a randomized, double-blind safety study comparing cetuximab produced from two manufacturing processes using the EXTREME study regimen.

BACKGROUND: Cetuximab, in combination with platinum chemotherapy plus 5-fluoruracil (5-FU), is approved for the first-line treatment of recurrent/metastatic squamous cell carcinoma of the head and neck (SCCHN). Cetuximab manufactured by ImClone (US commercial cetuximab) potentially results in higher systemic exposures than cetuximab manufactured by Boehringer Ingelheim (BI-manufactured cetuximab). This prospective, randomized, double-blind study compared the safety profiles of the two cetuximab formulations. METHODS: Patients with previously untreated locoregionally recurrent and/or metastatic SCCHN were randomly assigned to receive the same dose of US commercial cetuximab (Arm A) or BI-manufactured cetuximab (Arm B), each in combination with cisplatin or carboplatin plus 5-FU. The primary outcome was all-grade, all-cause treatment-emergent adverse events (TEAEs). RESULTS: The majority of patients experienced ≥ 1 TEAE, regardless of causality (Arm A: 75/77 patients, 97.4%; Arm B: 68/71 patients, 95.8%). TEAEs with the highest incidence included nausea, fatigue, and hypomagnesemia in both arms. The absolute risk difference between the two arms for patients experiencing at least one adverse event (AE) was 0.029 (p = 0.281, 95% confidence interval [CI]: -0.024, 0.082) for AEs regardless of causality and 0.005 (p = 0.915, 95% CI: -0.092, 0.103) for AEs possibly related to study drug. There were no significant differences between the two arms in the incidence of acneiform rash, cardiac events, infusion reactions, or hypomagnesemia. Overall survival, progression-free survival, and overall response rates were similar in the two arms. CONCLUSIONS: There were no clinically meaningful differences in safety between US commercial cetuximab and BI-manufactured cetuximab in combination with platinum-based therapy with 5-FU in patients with locoregionally recurrent and/or metastatic SCCHN. The use of US commercial cetuximab in this combination chemotherapy regimen did not result in any unexpected safety signals. The efficacy results of this study are consistent with the efficacy results of the cetuximab arm of the EXTREME study. TRIAL REGISTRATION: ClinicalTrials.gov NCT01081041 ; date of registration: March 3, 2010).

Multiplexed specific label-free detection of NCI-H358 lung cancer cell line lysates with silicon based photonic crystal microcavity biosensors.

We experimentally demonstrate label-free photonic crystal (PC) microcavity biosensors in silicon-on-insulator (SOI) to detect the epithelial-mesenchymal transition (EMT) transcription factor, ZEB1, in minute volumes of sample. Multiplexed specific detection of ZEB1 in lysates from NCI-H358 lung cancer cells down to an estimated concentration of 2 cells per micro-liter is demonstrated. L13 photonic crystal microcavities, coupled to W1 photonic crystal waveguides, are employed in which resonances show high Q in the bio-ambient phosphate buffered saline (PBS). When the sensor surface is derivatized with a specific antibody, the binding of the corresponding antigen from a complex whole-cell lysate generates a change in refractive index in the vicinity of the photonic crystal microcavity, leading to a change in the resonance wavelength of the resonance modes of the photonic crystal microcavity. The shift in the resonance wavelength reveals the presence of the antigen. The sensor cavity has a surface area of ∼11µm(2). Multiplexed sensors permit simultaneous detection of many binding interactions with specific immobilized antibodies from the same bio-sample at the same instant of time. Specificity was demonstrated using a sandwich assay which further amplifies the detection sensitivity at low concentrations. The device represents a proof-of-concept demonstration of label-free, high throughput, multiplexed detection of cancer cells with specificity and sensitivity on a silicon chip platform.

Depression and Anxiety Symptoms Relate to Distinct Components of Pain Experience among Patients with Breast Cancer.

Breast cancer is a leading cancer diagnosis among women worldwide, with more than 210,000 new cases and 40,000 deaths per year in the United States. Pain, anxiety, and depression can be significant factors during the course of breast cancer. Pain is a complex experience with sensory, affective, and cognitive dimensions. While depression and anxiety symptoms are relatively common among breast cancer patients, little is known about the relation between these psychiatric factors and distinct components of the pain experience. In the present study 60 females presenting to an NCI-designated Cancer Center with newly diagnosed breast cancer completed the Center for Epidemiological Studies 10-item Depression Scale, the State Instrument of the Spielberger State-Trait Anxiety Inventory, and the McGill Pain Questionnaire. Findings indicate that anxiety and depression are common among newly diagnosed breast cancer patients; furthermore, patients experience an appreciable amount of pain even before oncologic treatment starts. State anxiety serves as a predictor of the sensory dimension of the pain experience, whereas depression serves as a predictor of the affective dimension of the pain experience.

Definitive chemoradiotherapy for esophageal carcinoma.

Radiation therapy plays an important role in the treatment of esophageal cancer. Radiation therapy may be combined with chemotherapy, used as a component of induction therapy, used in the adjuvant setting, or used for palliation of advanced disease. Chemotherapy is also occasionally used as a solitary treatment modality for patients with esophageal cancer. Current treatment protocols include multiple agents, and agents directed against specific molecular targets have been investigated in clinical trials. This article discusses future directions related to the selection of radiation treatment protocols, novel targeted chemotherapeutic agents, and the selection of patients for surgery.

Adult-onset lower extremity weakness caused by venous malformation detected by magnetic resonance imaging.

INTRODUCTION: Symptomatic venous malformation (VM) of muscle in adults is rare and usually presents in childhood or adolescence as the individual is growing. We describe an atypical presentation of a malformation affecting the gastrocnemius muscle asymmetrically with onset in adulthood, which created a diagnostic challenge. Electromyography (EMG) and muscle biopsy did not fit clinically and MRI of the gastrocnemius led to the diagnosis. METHODS: The setting for the patient studied was a neuromuscular outpatient clinic. RESULTS: EMG showed decreased insertional activity and motor unit potential recruitment in the right gastrocnemius muscle. Muscle biopsy showed mild neurogenic changes. MRI demonstrated VM in the contralateral gastrocnemius muscle. CONCLUSIONS: This case represents a rare cause of atrophic weakness in adults, but muscle MRI should be considered when other tests are equivocal.

Percutaneous cement augmentation of a lytic lesion of C1 via posterolateral approach under CT guidance.

BACKGROUND CONTEXT: Percutaneous vertebroplasty (PV) can provide pain relief and biomechanical stabilization of lytic metastasis of the spine in selected patients. Percutaneous vertebroplasty of the atlas has been reported in only five cases and has been performed with different techniques and approaches. PURPOSE: To describe the technique we used to perform PV of a lytic lesion of the lateral mass of C1 under computed tomography, computed tomography angiography, and computed tomography fluoroscopy guidance with a posterolateral approach, sparing the vertebral artery (VA). STUDY DESIGN/SETTING: Technical note. METHODS: A 36-year-old woman with a history of intestinal carcinoid tumor presented with neck pain refractory to medical treatment. Radiological evaluation showed osteolytic destruction of the left lateral mass of the atlas, at the risk of collapse, with erosion of the VA canal. Under computed tomography and computed tomography angiography guidance, a percutaneous posterolateral oblique approach to the C1 left lateral mass was performed followed by cement augmentation under computed tomography fluoroscopy control. RESULTS: Complete cement filling of the osteolytic lesion was achieved. A cement leak was noted along the horizontal V3 segment of the left VA. Computed tomography angiography scan showed patency of the VA after the procedure. There were no clinical complications. The patient reported substantial pain relief and improved range of motion at 12 hours postprocedure, which remained stable at 2-month follow-up examination. CONCLUSIONS: Computed tomography-guided PV of C1 lytic lesion with posterolateral approach was effective in the described case for pain control and stabilization, and it may be a therapeutic option in selected patients to avoid occipitocervical fusion. This procedure requires good understanding of the anatomy and rigorous technique to avoid potential complications.

EGFR as a predictor of relapse in myxopapillary ependymoma.

Myxopapillary ependymoma (MPE) is a rare subtype of ependymoma in children. Though classified as a Grade I tumor, their unpredictable behavior and propensity for local and disseminated recurrence poses a therapeutic challenge. Till date no predictive molecular markers exist for such recurrence, especially with dissemination. We demonstrated that Epidermal Growth Factor Receptor (EGFR) expression was seen in relapsed MPE both at diagnosis and at recurrence and none in the nonrecurring tumors. This finding suggests EGFR could be a predictive biomarker for recurrence in MPE.

Disparity in hospice utilization by African American patients with cancer.

Patients with cancer represent the largest group of hospice users, making this population critically important in hospice research studies. Despite the potential benefits of hospice, many studies have noted lower levels of utilization among African Americans. The goal of this literature review was to determine whether this disparity exists within this population of patients with cancer. The largest studies focusing on multiple cancers found lower hospice use among African American patients with cancer. Disparities also existed after entry into hospice. Age, gender, geographic location, preference for aggressive care, and knowledge of hospice influenced hospice use by these patients. Since African American patients with cancer evidently use hospice at a lower rate, future studies should explore potential barriers to participation by this patient population and methods to remove these obstacles.

Case report of a patient with chemotherapy-induced peripheral neuropathy treated with manual therapy (massage).

PURPOSE: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, miserable, potentially severe, and often dose-limiting side effect of several first and second-line anti-cancer agents with little in the way of effective, acceptable treatment. Although mechanisms of damage differ, manual therapy (therapeutic massage) has effectively reduced symptoms and improved quality of life in patients with diabetic peripheral neuropathy. METHODS: Here, we describe application of manual therapy (techniques of effleurage and petrissage) to the extremities in a patient with grade 2 CIPN subsequent to prior treatment with docetaxel and cisplatin for stage III esophageal adenocarcinoma. Superficial cutaneous temperature was monitored using infrared thermistry as proxy for microvascular blood flow. RESULTS: By the end of the course of manual therapy without any change in medications, CIPN symptoms were greatly reduced to grade 1, with corresponding improvement in quality of life. Improvements in superficial temperature were observed in fingers and toes. CONCLUSIONS: Manual therapy was associated with almost complete resolution of the tingling and numbness and pain of CIPN in this patient. Concurrently increased superficial temperature suggests improvements in CIPN symptoms may have involved changes in blood circulation. To our knowledge, this is the first report of using manual therapy for amelioration of CIPN.

Inhibition of AMP-activated protein kinase pathway sensitizes human leukemia K562 cells to nontoxic concentration of doxorubicin.

Doxorubicin (Dox) is a commonly used anthracycline in many antitumor regimens. The dose related Dox-induced cardiotoxicity often poses challenge in clinical practice, lowering its dose and administering it in combination with other compound is an option. In this study, we found that a nontoxic concentration of Dox at 34.5 nM (20 ng/ml) combined with Compound C, an inhibitor used in AMP-activated protein kinase (AMPK) pathway, could kill human leukemia K562 cells. Additionally, this study confirmed that the combined effect was related to the inhibition of some key proteins such as AMPK and acetyl CoA carboxylase. Moreover, down-regulation of these key proteins in AMPK pathway using siRNA technology also sensitized K562 cells to nontoxic concentration of Dox. The study also showed that Dox at a concentration of 345.0 nM (200 ng/ml) or 862.0 nM (500 ng/ml) that is lower than a typical value of 1-2 microM Dox in patients could kill human leukemia K562 cells. Taken together, our results suggest that inhibition of AMPK pathway by Compound C or siRNA sensitizes K562 cells to nontoxic concentration of Dox which is much lower than typical concentration in plasma of clinical patients.