Reverse-Contrast Imaging and Targeted Radiation Therapy of Advanced Pancreatic Cancer Models.

PURPOSE: To evaluate the feasibility of delivering experimental radiation therapy to tumors in the mouse pancreas. Imaging and treatment were performed using combined CT (computed tomography)/orthovoltage treatment with a rotating gantry. METHODS AND MATERIALS: After intraperitoneal administration of radiopaque iodinated contrast, abdominal organ delineation was performed by x-ray CT. With this technique we delineated the pancreas and both orthotopic xenografts and genetically engineered disease. Computed tomographic imaging was validated by comparison with magnetic resonance imaging. Therapeutic radiation was delivered via a 1-cm diameter field. Selective x-ray radiation therapy of the noninvasively defined orthotopic mass was confirmed using γH2AX staining. Mice could tolerate a dose of 15 Gy when the field was centered on the pancreas tail, and treatment was delivered as a continuous 360° arc. This strategy was then used for radiation therapy planning for selective delivery of therapeutic x-ray radiation therapy to orthotopic tumors. RESULTS: Tumor growth delay after 15 Gy was monitored, using CT and ultrasound to determine the tumor volume at various times after treatment. Our strategy enables the use of clinical radiation oncology approaches to treat experimental tumors in the pancreas of small animals for the first time. We demonstrate that delivery of 15 Gy from a rotating gantry minimizes background healthy tissue damage and significantly retards tumor growth. CONCLUSIONS: This advance permits evaluation of radiation planning and dosing parameters. Accurate noninvasive longitudinal imaging and monitoring of tumor progression and therapeutic response in preclinical models is now possible and can be expected to more effectively evaluate pancreatic cancer disease and therapeutic response.

HSP90 inhibition is effective in breast cancer: a phase II trial of tanespimycin (17-AAG) plus trastuzumab in patients with HER2-positive metastatic breast cancer progressing on trastuzumab.

PURPOSE: HSP90 is a chaperone protein required for the stability of a variety of client proteins. 17-Demethoxygeldanamycin (17-AAG) is a natural product that binds to HSP90 and inhibits its activity, thereby inducing the degradation of these clients. In preclinical studies, HER2 is one of the most sensitive known client proteins of 17-AAG. On the basis of these data and activity in a phase I study, we conducted a phase II study of 17-AAG (tanespimycin) with trastuzumab in advanced trastuzumab-refractory HER2-positive breast cancer. EXPERIMENTAL DESIGN: We enrolled patients with metastatic HER2(+) breast cancer whose disease had previously progressed on trastuzumab. All patients received weekly treatment with tanespimycin at 450 mg/m(2) intravenously and trastuzumab at a conventional dose. Therapy was continued until disease progression. The primary endpoint was response rate by Response Evaluation Criteria in Solid Tumors (RECIST) criteria. RESULTS: Thirty-one patients were enrolled with a median age of 53 years and a median Karnofsky performance status (KPS) of 90%. The most common toxicities, largely grade 1, were diarrhea, fatigue, nausea, and headache. The overall response rate was 22%, the clinical benefit rate [complete response + partial response + stable disease] was 59%, the median progression-free survival was 6 months (95% CI: 4-9), and the median overall survival was 17 months (95% CI: 16-28). CONCLUSIONS: This is the first phase II study to definitively show RECIST-defined responses for 17-AAG in solid tumors. Tanespimycin plus trastuzumab has significant anticancer activity in patients with HER2-positive, metastatic breast cancer previously progressing on trastuzumab. Further research exploring this therapeutic interaction and the activity of HSP90 inhibitors is clearly warranted.

Phase II study of feasibility of dose-dense FEC followed by alternating weekly taxanes in high-risk, four or more node-positive breast cancer.

PURPOSE: To develop a potentially superior adjuvant chemotherapy regimen, we conducted a pilot study of dose-dense 5-fluorouracil, epirubicin, and cyclophosphamide (FEC) followed by weekly alternating taxanes. The primary objective was to determine the feasibility of the regimen; the secondary objective was to estimate the disease-free and overall survival. EXPERIMENTAL DESIGN: Patients with >/=4 node-positive breast cancer were studied. Treatment consisted of FEC at 500/100/500 mg/m(2), respectively, x6 at two-week intervals with granulocyte colony-stimulating factor, followed by weekly paclitaxel (80 mg/m(2)) alternating with docetaxel (35 mg/m(2)) x18. RESULTS: Between November 2001 and January 2003, 44 patients were enrolled. Median age was 46 years (range, 26-63 years), median number of positive nodes was 9 (range, 4-32), and median tumor size was 2.5 cm (range, 0.6-11.0 cm). Because of unexpected toxicities, the study was stopped when 17 (39%) had fully completed all of the planned treatment. Two of 17 (12%) developed grade 4 pericardial/grade 3 bilateral pleural effusions at treatment completion; both required pericardial window. The remaining patients were treated with taxanes using one of several standard dose and schedule combinations. Furthermore, 4 of 44 (9%) developed pneumonitis attributed to the FEC regimen. Hospital admissions were required for 12 of 44 (27%); 3 of 44 (7%) required blood transfusions. There were no treatment related deaths. Median disease-free and overall survival will not be estimatable because of early closure of study. CONCLUSION: FEC x6 at 2-week intervals followed by 18 weeks of alternating taxanes is not feasible at the doses tested. Other strategies are needed to improve adjuvant systemic chemotherapy.