Richard Tozer

Phase II Study of Ganitumab, a Fully Human Anti–Type-1 Insulin-Like Growth Factor Receptor Antibody, in Patients With Metastatic Ewing Family Tumors or Desmoplastic Small Round Cell Tumors

PURPOSE Ganitumab is a fully human monoclonal antibody against type-1 insulin-like growth factor receptor (IGF1R). An open-label phase II study was conducted to evaluate the efficacy and safety of ganitumab monotherapy in patients with metastatic Ewing family tumors (EFT) or desmoplastic small round cell tumors (DSRCT). PATIENTS AND METHODS Patients ≥16 years of age with relapsed or refractory EFT or DSRCT received 12 mg/kg of ganitumab every 2 weeks. Objective response rate (ORR) was the primary end point. Secondary end points included clinical benefit rate (CBR = complete + partial responses + stable disease [SD] ≥ 24 weeks) and safety and pharmacokinetic profiles of ganitumab. The relationship between tumor response and EWS gene translocation status and IGF-1 levels was evaluated. RESULTS Thirty-eight patients (22 with EFT; 16 with DSRCT) received one or more doses of ganitumab. Twenty-four patients (63%) experienced ganitumab-related adverse events. Grade 3 related events included hyperglycemia (n = 2), thrombocytopenia (n = 5), neutropenia (n = 2), leukopenia (n = 1), and transient ischemic attack (n = 1). There were no grade 4 or 5 treatment-related events. Of 35 patients assessed for response, two had partial responses (ORR, 6%) and 17 (49%) had SD. Four patients had SD ≥ 24 weeks, contributing to a CBR of 17%. The pharmacokinetic profile of ganitumab was similar to that observed in the first-in-human trial. Elevation of IGF-1 levels was observed postdose. EWS-Fli1 translocations were analyzed by RNA sequencing and fluorescent in situ hybridization, and novel translocations were observed in EFT and DSCRT. No apparent relationship between tumor response and IGF-1 levels or EWS gene translocations was observed. CONCLUSION Ganitumab was well tolerated and demonstrated antitumor activity in patients with advanced recurrent EFT or DSRCT.

The Initial Health Assessment: an intervention to identify the supportive care needs of cancer patients

BackgroundThe first step in effective supportive care delivery is an assessment of patient needs. The Initial Health Assessment Form (IHA) was developed to aid clinicians in recognition and documentation of a patients supportive care needs during their first visit to a comprehensive cancer centre. The purpose of this study was to determine the relative effectiveness of this instrument as compared to routine practice.MethodsA before-after study was performed. Charts of consecutive patients with newly diagnosed cancer attending the Hamilton Regional Cancer Centre were selected randomly. Each chart was reviewed to determine the documentation at the initial patient assessment of 22 supportive care items under eight domains of need: physical, psychological, daily living, social, financial, informational, special needs and personal resources. The pre-intervention evaluation (T1) occurred over a 3-month period followed by the introduction of the IHA into clinical practice. Three months after its introduction, the post-intervention (T2) evaluation took place over the ensuing 3 months.ResultsA total of 306 charts were evaluated (153 each in T1 and T2). Patients from the two time periods were comparable with respect to background demographic variables. Introduction of the IHA increased the mean documentation of supportive care needs and resources from 26% in T1 to 49% in T2 (p=0.001). Significant improvements were found in all domains of need. Despite improvements, documentation of assessment continued to remain low for daily living, social, financial, and informational needs.ConclusionsThe IHA improved documentation of supportive care needs and resources. There is still room for improvement.

Immunolocalization of matrix metalloproteinases and their inhibitors in clinical specimens of bone metastasis from breast carcinoma

Matrix metalloproteinases (MMPs) are essential in several stages of the metastatic process, and in normal bone development and remodeling. We explored whether the interaction between tumor cells and bone leads to changes in MMP and tissue inhibitor of MMP (TIMP) expression thus affecting osteolysis in metastatic bone disease. Using immunohistochemistry we have investigated the MMP/TIMP expression in tumor cells, fibroblasts, osteoblasts and osteoclasts. Thirty one specimens of bone metastasis from breast carcinoma were stained for MMP-1, -2, -9, MT1-MMP and TIMP- 1, and -2 and compared with staining in normal breast tissue, primary breast carcinoma and normal bone. Specimens came from patients in three clinical scenarios: from open biopsies without or with pathological fracture, or bone marrow biopsies containing tumor from patients with pancytopenia but without clinical evidence of osteolysis. By bone histomorphometry the latter group showed a heavy tumor load not different from the open biopsy groups but displayed little active bone resorption and low numbers of osteoclasts. Cell type-specific MMP/TIMP expression was observed and the staining patterns were comparable between the three groups of patients. Though no major differences in the MMP/TIMP staining of tumor cells and fibroblasts were observed between bone metastasis and primary tumor, we showed that tumor cells do express MMPs capable of degrading bone matrix collagen. The number and activity of osteoclasts and osteoblasts was increased dramatically in bone metastases, their MMP/TIMP profiles, however, were not different from normal bone, suggesting that the mechanism of bone degradation by osteoclasts is not different from normal bone remodelling.

Expression of Ets-related transcription factors and matrix metalloproteinase genes in human breast cancer cells

The expression levels of ets and MMP genes was examined in two breast cancer cell lines of differing invasive potential. The more invasive MDA-MB-231 cell line had higher levels of Ets-1, Ets-2, PEA3, ERM, Tel, Net, MMP-13 and -14 mRNA than MCF-7 cells. MMP-1, -3 and -16 mRNAs were expressed equally. TPA stimulated MMP-1, -9 and TIMP-1 mRNA expression in both cell lines. MMP-2 and MMP-7 mRNAs were not detected in either cell line. The Ets-1 protein was only detected in MDA-MB-231 cells and its level increased following TPA stimulation. TPA induced MMP-9 activity in MCF-7 cells and increased its activity in MDA-MB-231 cells, however, MMP-2 activity was not detected.

Reproducibility of Peripheral Quantitative Computed Tomography Measurements at the Radius and Tibia in Healthy Pre- and Postmenopausal Women

Purpose The objectives of this study were to utilise the XCT-2000 pQCT scanner to determine the mean values and the reproducibility of in vivo total, trabecular, and cortical volumetric bone measurements at distal and diaphyseal sites of the radius and the tibia, as well as calf muscle and subcutaneous fat areas, in healthy pre- and postmenopausal women. Methods Twenty-nine women (14 premenopausal and 15 postmenopausal) were recruited to participate in this study. Distal and diaphyseal sites of the radius (at 4% and 20% of the length of the radius) and tibia (at 4%, 38%, and 66% of the length of the tibia) were examined. Results The root mean square coefficient of variation for measurements at the distal tibia gave the most favorable reproducibility values for total (1.5%) and trabecular (1.6%) density, whereas the diaphyseal tibia showed the most favorable reproducibility value for cortical density (0.3%). The root mean square coefficients of variation for measurements of muscle and fat cross-sectional areas at the calf were 0.6% and 0.7%, respectively. At the distal tibia, the mean values for total (P < .05) and trabecular (P < .01) density were significantly lower in postmenopausal women than in premenopausal women. Conclusions The data presented here indicate that XCT-2000 pQCT scans at the tibia provide highly reproducible measurements of total, cortical, and trabecular bone as well as muscle and fat cross-sectional areas. Furthermore, significant differences in volumetric bone measurements between healthy pre- and postmenopausal women were evident only at the distal tibia, suggesting that this site warrants further study.

Cortical and trabecular bone at the radius and tibia in postmenopausal breast cancer patients: A Peripheral Quantitative Computed Tomography (pQCT) study

Bone morbidity associated with antineoplastic treatment is a significant health concern for postmenopausal breast cancer patients. Trials have demonstrated that adjuvant therapy with an Aromatase Inhibitor is associated with an increase in musculoskeletal disorders and bone fractures. The objective of this study was to utilize Peripheral Quantitative Computed Tomography (pQCT) to assess in vivo trabecular and cortical volumetric bone at peripheral skeletal sites in healthy postmenopausal women and breast cancer patients prescribed Anastrozole. Fifty-eight women were recruited for this study: 27 breast cancer patients and 31 healthy control participants. pQCT measurements were taken at distal and diaphyseal sites of the radius and tibia using a Stratec XCT-2000 pQCT scanner. Bone measurement values for total density and total content at the 4% radius; total and cortical content as well as cortical density at the 20% radius; total density at the 4% tibia; and cortical density at the 38% tibia were found to be significantly lower in breast cancer patients. Moreover, the duration of time on Anastrozole showed a significant negative correlation with the following measurements: total content at the 4% radius (r=-0.36, p<0.01); total content (r=-0.33, p<0.05), cortical content (r=-0.34, p<0.05) and cortical density (r=-0.44, p<0.01) at the 20% radius; as well as cortical density (r=-0.39, p<0.01) and cortical content (r=-0.27, p<0.05) at the 38% tibia. Overall, the breast cancer patients demonstrated significantly lower values for volumetric bone density and content at the radius and tibia compared with healthy postmenopausal women. Furthermore, this novel study found adverse effects from Anastrozole treatment primarily in cortical bone.