A multicenter, open-label, randomized, phase II study of cediranib with or without lenalidomide in iodine 131-refractory differentiated thyroid cancer.

BACKGROUND: Multitargeted tyrosine kinase inhibitors (TKIs) of the vascular endothelial growth factor receptor (VEGFR) pathway have activity in differentiated thyroid cancer (DTC). Lenalidomide demonstrated preliminary efficacy in DTC, but its safety and efficacy in combination with VEGFR-targeted TKIs is unknown. We sought to determine the safety and efficacy of cediranib, a VEGFR-targeted TKI, with or without lenalidomide, in the treatment of iodine 131-refractory DTC. PATIENTS AND METHODS: In this multicenter, open-label, randomized, phase II clinical trial, 110 patients were enrolled and randomized to cediranib alone or cediranib with lenalidomide. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rate, duration of response, toxicity, and overall survival (OS). Patients (≥18 years of age) with DTC who were refractory to further surgical or radioactive iodine (RAI) therapy as reviewed at a multispecialty tumor board conference, and evidence of disease progression within the previous 12 months and no more than one prior line of systemic therapy were eligible. RESULTS: Of the 110 patients, 108 started therapy and were assessable for efficacy. The median PFS was 14.8 months [95% confidence interval (CI) 8.5-23.8 months] in the cediranib arm and 11.3 months (95% CI 8.7-18.9 months) in the cediranib with lenalidomide arm (P = 0.36). The 2-year OS was 64.8% (95% CI 43.3% to 86.4%) and 75.3% (95% CI 59.4% to 91.0%), respectively (P = 0.80). The serious adverse event rate was 41% in the cediranib arm and 46% in the cediranib with lenalidomide arm. CONCLUSIONS: Single-agent therapy with cediranib showed promising efficacy in RAI-refractory DTC similar to other VEGFR-targeted TKIs, while the addition of lenalidomide did not result in clinically meaningful improvements in outcomes.

Phase II trial of dasatinib for recurrent or metastatic c-KIT expressing adenoid cystic carcinoma and for nonadenoid cystic malignant salivary tumors.

BACKGROUND: Adenoid cystic carcinoma (ACC) is a subtype of malignant salivary gland tumors (MSGT), in which 90% of cases express cKIT. Dasatinib is a potent and selective inhibitor of five oncogenic protein tyrosine kinases (PTKs)/kinase families including cKIT. We conducted a phase II study to determine the antitumor activity of dasatinib in ACC and non-ACC MSGT. PATIENTS AND METHODS: In a two-stage design, patients with progressive, recurrent/metastatic ACC (+cKIT) and non-ACC MSGT (separate cohort) were treated with dasatinib 70 mg p.o. b.i.d. Response was assessed every 8 weeks using RECIST. RESULTS: Of 54 patients: 40 ACC, 14 non-ACC (1, ineligible excluded); M:F = 28 : 26, median age 56 years (range 20-82 years), ECOG performance status 0 : 1 : 2 = 24 : 28 : 2, prior radiation: 44, prior chemotherapy: 21. The most frequent adverse events (AEs) (as % of patients, worst grade 2 or higher) were: fatigue (28%), nausea (19%), headache (15%), lymphopenia (7%), dyspnea (11%), alanine aminotransferase increased (7%), anorexia (7%), vomiting (7%), alkaline phosphatase increased (6%), diarrhea (6%), neutropenia (6%), and noncardiac chest pain (6%). No grade 4 AE occurred, 15 patients experienced a grade 3 AE, primarily dyspnea (5) and fatigue (4), and cardiac toxicity (1 prolonged QTc). Among ACC patients, best response to dasatinib: 1 patient (2.5%) had partial response, 20 patients (50%) had stable disease (SD) (3-14 months), 12 patients (30%) had PD, 2 withdrew, 3 discontinued therapy due to AE, and 2 died before cycle 2. Median progression-free survival was 4.8 months. Median overall survival was 14.5 months. For 14 assessable non-ACC patients, none had objective response, triggering early stopping rule. Seven had SD (range 1-7 months), 4 PD, 2 discontinued therapy due to AE, and 1 died before cycle 2. CONCLUSION: Although there was only one objective response, dasatinib is well tolerated, with tumor stabilization achieved by 50% of ACC patients. Dasatinib demonstrated no activity in non-ACC MSGT.

CT perfusion can predict overexpression of CXCL8 (interleukin-8) in head and neck squamous cell carcinoma.

BACKGROUND AND PURPOSE: Increased angiogenesis in head and neck squamous cell carcinoma correlates to more aggressive tumors with increased morbidity. Because both elevated blood flow and high serum CXCL8 levels are correlated with increased angiogenesis, our objective was to see if elevated blood flow measured with CT perfusion correlated with CXCL8 levels, thereby helping to identify candidates for targeted therapies that inhibit the Bcl-2 proangiogenic pathway associated with CXCL8. MATERIALS AND METHODS: Seven patients with locally recurrent or metastatic head and neck squamous cell carcinoma were enrolled in the trial. These patients underwent CT perfusion and the following parameters were measured: blood volume, blood flow, capillary permeability, and MTT; relative values were calculated by dividing by normal-appearing muscle. Serum was drawn for CXCL8 enzyme-linked immunosorbent assay analysis in these patients. RESULTS: There was a significant positive correlation between the CXCL8 levels and relative blood flow (r = 0.94; P = .01). No correlation was found between CXCL8 and relative blood volume, relative capillary permeability, or relative MTT. CONCLUSIONS: Relative blood flow may be useful as a surrogate marker for elevated CXCL8 in patients with head and neck squamous cell cancer. Patients with elevated relative blood flow may benefit from treatment targeting the Bcl-2 proangiogenic pathways.

Cetuximab and bevacizumab: preclinical data and phase II trial in recurrent or metastatic squamous cell carcinoma of the head and neck.

BACKGROUND: We evaluated combined targeting with cetuximab, an anti-epidermal growth factor receptor (EGFR) monoclonal antibody, and bevacizumab, an anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in squamous cell carcinoma of the head and neck (SCCHN). PATIENTS AND METHODS: The combination was studied in human endothelial cells and head and neck and lung cancer xenograft model systems. Patients with recurrent or metastatic SCCHN were treated with weekly cetuximab and bevacizumab, 15 mg/kg on day 1 given intravenously every 21 days, until disease progression. Analysis of tumor biomarkers and related serum cytokines was performed. RESULTS: Cetuximab plus bevacizumab enhanced growth inhibition both in vitro and in vivo, and resulted in potent reduction in tumor vascularization. In the clinical trial, 46 eligible patients were enrolled. The objective response rate was 16% and the disease control rate 73%. The median progression-free survival and overall survival were 2.8 and 7.5 months, respectively. Grade 3-4 adverse events were expected and occurred in less than 10% of patients. transforming growth factor alpha, placenta-derived growth factor, EGFR, VEGFR2 increased and VEGF decreased after treatment but did not correlate with treatment efficacy. CONCLUSIONS: Cetuximab and bevacizumab are supported by preclinical observations and are well tolerated and active in previously treated patients with SCCHN.

Treatment response assessment of head and neck cancers on CT using computerized volume analysis.

BACKGROUND AND PURPOSE: Head and neck cancer can cause substantial morbidity and mortality. Our aim was to evaluate the potential usefulness of a computerized system for segmenting lesions in head and neck CT scans and for estimation of volume change of head and neck malignant tumors in response to treatment. MATERIALS AND METHODS: CT scans from a pretreatment examination and a post 1-cycle chemotherapy examination of 34 patients with 34 head and neck primary-site cancers were collected. The computerized system was developed in our laboratory. It performs 3D segmentation on the basis of a level-set model and uses as input an approximate bounding box for the lesion of interest. The 34 tumors included tongue, tonsil, vallecula, supraglottic, epiglottic, and hard palate carcinomas. As a reference standard, 1 radiologist outlined full 3D contours for each of the 34 primary tumors for both the pre- and posttreatment scans and a second radiologist verified the contours. RESULTS: The correlation between the automatic and manual estimates for both the pre- to post-treatment volume change and the percentage volume change for the 34 primary-site tumors was 0.95, with an average error of -2.4 ± 8.5% by automatic segmentation. There was no substantial difference and specific trend in the automatic segmentation accuracy for the different types of primary head and neck tumors, indicating that the computerized segmentation performs relatively robustly for this application. CONCLUSIONS: The tumor size change in response to treatment can be accurately estimated by the computerized segmentation system relative to radiologists' manual estimations for different types of head and neck tumors.

Management of patients with adrenal cancer: recommendations of an international consensus conference.

Adrenocortical carcinomas are rare, highly malignant tumors that account for only 0.2% of deaths due to cancer. Given the limited number of patients seen in most medical centers with this diagnosis, series usually reported are small and clinical trials not randomized or blinded. In an attempt to answer important questions concerning the management of patients with adrenal cancer, a consensus conference was organized and held at the University of Michigan in Ann Arbor, MI, 11-13 September 2003, with the participation of an international group of physicians who had reported on the largest series of patients with this disease and who had recognized basic and clinical research expertise in adrenal cortical cancer. Totally 43 questions were addressed by the presenters and recommendations discussed in plenary and breakout sessions. Evidence for the recommendations of this conference was at the 2-4+ level and based on available literature and participants' experience. In addition to setting up guidelines in specific areas of the diagnosis and treatment of adrenal cancer, the conference recommended and initiated the planning of an international prospective trial for treatment of patients with adrenal cancer in stages III and IV. In terms of new therapies, first trials of dendritic cell therapy in human subjects with adrenal cancer have been started, but it is too early to comment on efficacy. Different strategies of immunotherapy, including DNA vaccination are currently being tried in animal models. There are no clinical gene therapy trials for human adrenal cortical cancer. The adrenals are a preferred target for adenovirus and the results of gene therapy in preclinical studies are promising. In addition, there is evidence that histone deacetylase inhibitors can further enhance the rate of adenoviral infectivity in human adrenal cancer cells. Testing of retroviral vectors, non-viral vectors, small interfering RNA technology, and combined approaches could be performed in various laboratories. Anti-angiogenic substances have only been applied in preclinical studies. The use of these and other agents in the treatment of adrenal cancer should be hypothesis-driven and based on a thorough analysis of tumor biology.

Therapeutic advances in small cell lung cancer.

Small cell lung cancer (SCLC) is characterised by neuroendocrine differentiation, early metastatic potential and initial responsiveness to cytotoxic therapy. Unfortunately, despite recent therapeutic advances, most patients relapse and the overall five-year survival rate is only 5%. Standard treatment of SCLC consists of platinum-based combination chemotherapy, with thoracic irradiation added for patients with limited-stage disease. Several newer chemotherapeutic drugs have recently been shown to have significant activity in patients with untreated or relapsed SCLC. These agents include: the topoisomerase I inhibitors, topotecan and irinotecan; the taxanes, paclitaxel and docetaxel; the pyrimidine analogue, gemcitabine; and the vinca alkaloid, vinorelbine. Recent advances in our understanding of the molecular events involved in the pathogenesis and progression of SCLC have led to the identification of a variety of potential targets for novel therapeutic interventions. Strategies aimed at inhibiting the myriad of growth factor pathways that control the proliferation of SCLC cells, include: broad spectrum neuropeptide antagonists (e.g., substance P analogues); growth factor/receptor-specific inhibitors (e.g., anti-GRP monoclonal antibodies, bradykinin antagonist dimers); and a variety of selective protein kinase inhibitors. The importance of cell death pathways in carcinogenesis and treatment-resistance has led to several novel strategies targeting apoptotic mediators, such as bcl-2, that are frequently dysregulated in SCLC (e.g., bcl-2 antisense). Our current challenges are to further refine these promising therapeutic strategies, efficiently evaluate their activity in the clinical setting and integrate them into more effective treatment regimens to improve the overall prognosis of patients with SCLC.