Phase I clinical and pharmacodynamic evaluation of oral CI-1033 in patients with refractory cancer.

PURPOSE: To determine the tolerability and pharmacokinetics of CI-1033 given daily for 7 days of a 21-day cycle. Tumor response and changes in erbB receptor tyrosine kinase activity in tumor and skin tissue were examined, and modulation of potential biomarkers in plasma was explored. DESIGN: This was a dose-finding phase I study in patients with advanced solid malignancies. Patients were evaluated for safety, pharmacokinetics, and tumor response. Pharmacodynamic markers, such as Ki67, p27, and erbB receptor status, were assessed in tumor and skin tissue using immunohistochemical and immunoprecipitation methodologies. Plasma biomarkers HER2, vascular endothelial growth factor, interleukin-8, and matrix metalloproteinase-9 were evaluated using immunologic techniques. RESULTS: Fifty-three patients were enrolled in the study. Dose-limiting toxicity (emesis, persistent rash, and mouth ulcer) was observed at 750 mg. The maximum tolerated dose was 650 mg. There were no confirmed objective responses. CI-1033 treatment showed down-regulation of epidermal growth factor receptor, HER2, and Ki67 in a variety of tumor tissues and up regulation of p27 in skin tissue. Plasma HER2 was reduced following CI-1033 administration, but no consistent change in vascular endothelial growth factor, interleukin-8, or matrix metalloproteinase-9 was noted. CI-1033 plasma concentrations were proportional to dose. CONCLUSION: The safety and pharmacokinetic profile of CI-1033 was favorable for multidose oral administration. Evidence of modulation of erbB receptor activity in tumor and skin tissue was accompanied by changes in markers of proliferation and cell cycle inhibition. Additional clinical trials are warranted in defining the role of CI-1033 in the treatment of cancer and further assessing the utility of antitumor markers.

Phase II study of a liposome-entrapped cisplatin analog (L-NDDP) administered intrapleurally and pathologic response rates in patients with malignant pleural mesothelioma.

PURPOSE: To determine pathologic response rates to liposome-entrapped cis-bisneodecanoato-trans-R,R-1,2-diaminocyclohexane platinum(II) (L-NDDP) administered intrapleurally in patients with malignant pleural mesothelioma. PATIENTS AND METHODS: Thirty-three patients with malignant pleural mesothelioma and free-flowing pleural effusions received intrapleural L-NDDP once every 3 weeks at a dose of 450 mg/m2. Thoracoscopic evaluation with pleural biopsies was performed before therapy and then after every two cycles. The primary end point was pathologic response as determined by thoracoscopic biopsy. RESULTS: After at least two cycles, post-treatment pleural biopsy analysis was negative in 14 patients for a pathologic response rate of 42% (95% CI, 25% to 61%). Median survival was 11.2 months. There were three treatment-related deaths secondary to peritonitis, cellulitis at the thoracoscopy site, and empyema. Grade 3 nonhematologic toxicities included infection, fever, dyspnea, and anorexia, which occurred in five (15%), one (3%), one (3%), and one (3%) patients, respectively. There were no grade 4 nonhematologic toxicities. Grade 3 or 4 neutropenia, thrombocytopenia, and anemia occurred in five (15%), three (9%), and two (6%) patients, respectively. Two patients with pathologic responses subsequently underwent pleural decortication. Both surgical specimens revealed residual tumor in regions that were not in direct communication with the pleural space. CONCLUSION: Intrapleural L-NDDP therapy in this patient population is feasible with significant but manageable toxicity. Although pathologic responses are highly encouraging, areas of mesothelioma that are not in direct communication with the pleural space will evade drug exposure and limit efficacy in some patients. The optimal role of intrapleural L-NDDP therapy currently remains to be determined.

Development of Late Toxicities in Patients with Oral Tongue Cancer Treated with Surgical Resection and Adjuvant Radiation Therapy.

OBJECTIVES: The late effects of RT are not well reported in patients with oral tongue cancer (OTC). This study reports the incidence of late effects and factors associated with the development of late effects in OTC patients. METHODS: Patients with OTC treated in our institution from 2003 to 2013 were evaluated. The association between RT doses, including mandible maximum and minimum doses and total 3D maximum dose, and late toxicity, defined as development of osteoradionecrosis (ORN), percutaneous endoscopic gastrostomy (PEG) tube dependence for >6 months after treatment, and narcotic dependency >6 months posttreatment were assessed using both univariate and multivariable (MV) analysis. RESULTS: Seventy-six patients with OTC (45% males and 55% females) were treated with definitive surgical resection followed by adjuvant RT. The median follow-up was 4.3 years. Combined late toxicities were reported in 38% of patients. Thirty-four percent of the patients had narcotic dependency and, 3.9% of the patients had ORN of the mandible. Thirteen percent of patients developed PEG tube dependency that was significantly associated with a higher 3D maximum radiation dose on univariate analysis (p < 0.01). On MV analysis, 3D maximum dose remained significantly associated with long-term PEG tube dependency (p = 0.05). CONCLUSION: Patients with OTC treated with adjuvant RT are at significant risk for development of late toxicities. Increasing maximum dose is associated with long-term PEG tube dependence, and care should be taken to reduce the "hot spot" within radiation treatment plans as much as possible.

Prevention of radiation-induced oral cavity mucositis by plasmid/liposome delivery of the human manganese superoxide dismutase (SOD2) transgene.

Oral cavity mucositis is a major toxicity of radiation therapy for head and neck cancer. In the present mouse model studies, we evaluated intraoral administration of SOD2-PL complexes 24 h before single-fraction 30-Gy irradiation for the prevention of oral cavity mucositis. Expression of the human SOD2 transgene in the oral cavity of C3H/HeNsd mice was demonstrated by nested reverse transcriptase polymerase chain reaction (RT-PCR). Mice treated intraorally with bacterial beta-galactosidase gene-plasmid/liposome (LacZ-PL) or hemagglutinin (HA)-manganese superoxide dismutase-plasmid/liposome (HA-SOD2-PL) demonstrated LacZ or HA-SOD2 expression, respectively, 24 h after injection. In a second strain of mouse, SOD2-PL-treated female athymic nude mice demonstrated significantly decreased ulceration at day 5 after 30 Gy, compared to LacZ-PL-injected, irradiated mice or irradiated controls. No further reduction in radiation-induced ulceration was detected in mice treated with both SOD2-PL and 10 mg/kg of amifostine (WR-2721) 30 min before 30 Gy compared to SOD2-PL alone. No significant protection of orthotopically transplanted murine squamous cell carcinoma (SCC-VII) tumors was detected in mice that received SOD2-PL treatment before 18 Gy. Thus overexpression of human SOD2 in the oral cavity mucosa can prevent radiation-induced mucositis with no detectable compromise in the therapeutic response of orthotopically transplanted tumors.

Luteolin nanoparticle in chemoprevention: in vitro and in vivo anticancer activity.

Cancer prevention (chemoprevention) by using naturally occurring dietary agents has gained immense interest because of the broad safety window of these compounds. However, many of these compounds are hydrophobic and poorly soluble in water. They frequently display low bioavailability, poor systemic delivery, and low efficacy. To circumvent this problem, we explored a novel approach toward chemoprevention using nanotechnology to deliver luteolin, a natural compound present in green vegetables. We formulated water-soluble polymer-encapsulated Nano-Luteolin from hydrophobic luteolin, and studied its anticancer activity against lung cancer and head and neck cancer. In vitro studies demonstrated that, like luteolin, Nano-Luteolin inhibited the growth of lung cancer cells (H292 cell line) and squamous cell carcinoma of head and neck (SCCHN) cells (Tu212 cell line). In Tu212 cells, the IC50 value of Nano-Luteolin was 4.13 µmol/L, and that of luteolin was 6.96 µmol/L. In H292 cells, the IC50 of luteolin was 15.56 µmol/L, and Nano-Luteolin was 14.96 µmol/L. In vivo studies using a tumor xenograft mouse model demonstrated that Nano-Luteolin has a significant inhibitory effect on the tumor growth of SCCHN in comparison to luteolin. Our results suggest that nanoparticle delivery of naturally occurring dietary agents like luteolin has many advantages and may have potential application in chemoprevention in clinical settings.

A reexamination of active and passive tumor targeting by using rod-shaped gold nanocrystals and covalently conjugated peptide ligands.

The targeted delivery of nanoparticles to solid tumors is one of the most important and challenging problems in cancer nanomedicine, but the detailed delivery mechanisms and design principles are still not well understood. Here we report quantitative tumor uptake studies for a class of elongated gold nanocrystals (called nanorods) that are covalently conjugated to tumor-targeting peptides. A major advantage in using gold as a "tracer" is that the accumulated gold in tumors and other organs can be quantitatively determined by elemental mass spectrometry (gold is not a natural element found in animals). Thus, colloidal gold nanorods are stabilized with a layer of polyethylene glycols (PEGs) and are conjugated to three different ligands: (i) a single-chain variable fragment (ScFv) peptide that recognizes the epidermal growth factor receptor (EGFR); (ii) an amino terminal fragment (ATF) peptide that recognizes the urokinase plasminogen activator receptor (uPAR); and (iii) a cyclic RGD peptide that recognizes the a(v)ß(3) integrin receptor. Quantitative pharmacokinetic and biodistribution data show that these targeting ligands only marginally improve the total gold accumulation in xenograft tumor models in comparison with nontargeted controls, but their use could greatly alter the intracellular and extracellular nanoparticle distributions. When the gold nanorods are administered via intravenous injection, we also find that active molecular targeting of the tumor microenvironments (e.g., fibroblasts, macrophages, and vasculatures) does not significantly influence the tumor nanoparticle uptake. These results suggest that for photothermal cancer therapy, the preferred route of gold nanorod administration is intratumoral injection instead of intravenous injection.

Neoadjuvant chemotherapy for squamous cell carcinoma of the oral tongue in young adults: a case series.

BACKGROUND: Squamous cell carcinoma of the oral tongue (SCCOT) in the young population has emerged as a growing worldwide health problem. Standard therapies, consisting primarily of surgery with possible adjuvant radiotherapy, have resulted in only modest improvements in survival in recent decades, whereas the treatments for SCCOT continue to impair oral function. With the increased use and improved functional results of neoadjuvant chemotherapy in the treatment of squamous cell carcinoma of other upper aerodigestive tract sites, we have reviewed our experience with neoadjuvant chemotherapy in young patients with SCCOT. METHODS: A retrospective review was conducted of all patients younger than 45 years (N = 49) with previously untreated SCCOT evaluated at a comprehensive cancer center from July 1995 to August 2001. Charts were reviewed to obtain demographic data, comorbidities, nutritional status, tumor status, treatment and response information, and follow-up data. RESULTS: Fifteen patients were identified who received neoadjuvant chemotherapy with taxane-based regimens before undergoing glossectomy and neck dissection. Thirteen of these patients (87%) exhibited stage III or IV disease at presentation, and all exhibited at least a partial response at the primary site. Pathologically positive nodes were identified in only six patients (40%), although 13 (87%) had clinically or radiographically suspicious nodes at presentation. Adjuvant radiation therapy was administered to seven patients (47%). With a median follow-up of 39 months, no patient has had local or regional recurrence, although three patients (20%) have had distant metastases develop; one patient with an isolated distant metastasis was successfully salvaged with radiation. By comparison during the same period, 34 young adult patients with SCCOT were treated with surgery with or without postoperative radiotherapy but without the use of chemotherapy. Although these patients had lower T classifications (18% vs 67% T3/T4; p = .0007), incidence of nodal metastases (15% vs 87% N+; p < .0001), and overall disease stage (24% vs 87% stage III/IV; p < .0001) than the neoadjuvant chemotherapy group, the overall survival (82%), disease-specific survival (88%), and recurrence-free survival (82%) of the surgery-first group was similar to that of the neoadjuvant chemotherapy group (87%, 87%, and 80%, respectively). CONCLUSIONS: This retrospective investigation demonstrates that neoadjuvant chemotherapy with taxane-based regimens may play a role in the successful treatment of SCCOT in young adult patients. Ultimately, this treatment plan may lead to improved functional outcomes in young patients with SCCOT by allowing function-sparing surgery and avoiding postoperative radiotherapy, without sacrificing disease control and survival, but a prospective trial is needed. We have initiated a prospective clinical trial to further investigate the impact of neoadjuvant chemotherapy in patients younger than 50 with SCCOT.