Rodolfo Nunez

Phase I/II Study of Trastuzumab in Combination With Everolimus (RAD001) in Patients With HER2-Overexpressing Metastatic Breast Cancer Who Progressed on Trastuzumab-Based Therapy

PURPOSE Trastuzumab resistance has been linked to activation of the phosphoinositol 3-kinase (PI3K) pathway. Phosphatase and tensin homolog (PTEN) is a dual phosphatase that counteracts the PI3K function; PTEN loss leads to activation of the Akt cascade and the downstream mammalian target of rapamycin (mTOR). Preclinical studies demonstrated that mTOR inhibition sensitized the response to trastuzumab in mice with HER2 overexpressing and PTEN-deficient breast xenografts. Our trial evaluated the safety and efficacy of the combination of everolimus and trastuzumab in women with HER2-overexpressing metastatic breast cancer (MBC) that progressed on trastuzumab-based therapy. PATIENTS AND METHODS This represents a pooled analysis (n = 47), stemming from two trials that occurred concurrently in The University of Texas MD Anderson Cancer Center, Beth Israel Deaconess Medical Center, and Dana-Farber Cancer Institute. Patients with HER2-overexpressing MBC who had progressed on trastuzumab-based therapy received trastuzumab every 3 weeks in combination with daily everolimus. RESULTS Among 47 patients, the combination of everolimus and trastuzumab provided partial responses in seven patients (15%) and persistent stable disease (lasting 6 months or longer) in nine patients (19%), resulting in a clinical benefit rate of 34%. The median progression-free survival (PFS) was 4.1 month. Fatigue, infection, and mucositis were the predominant nonhematologic toxicities. Trastuzumab did not have significant influence on the pharmacokinetic profile of everolimus. Patients with PTEN loss demonstrated decreased overall survival (P = .048). However, PFS was not affected by PTEN loss. CONCLUSION Inhibition of mTOR results in clinical benefit and disease response in patients with trastuzumab-resistant HER2-overexpressing MBC.

Yttrium 90 Resin Microspheres for the Treatment of Unresectable Colorectal Hepatic Metastases after Failure of Multiple Chemotherapy Regimens: Preliminary Results

PURPOSE Responses to liver-directed therapy with yttrium 90 microspheres (SIR-Spheres) and adjuvant intraarterial chemotherapy have occurred in patients with unresectable colorectal hepatic metastases who had received less than one chemotherapy regimen. Now, SIR-Spheres are being used to treat patients with advanced disease who have received multiple chemotherapy regimens. A retrospective analysis was performed to determine the technical feasibility of SIR-Sphere treatment in this population. MATERIALS AND METHODS The medical records of 12 patients with hepatic metastatic disease and intrahepatic progression after multiple chemotherapy regimens for unresectable colorectal hepatic metastases who were treated with one or two infusions of SIR-Spheres were retrospectively analyzed for demographics, tumor characteristics, treatment details, response, and survival. RESULTS Twelve patients underwent 17 outpatient infusions of SIR-Spheres. Percent hepatic tumor volume was less than 25% in four patients, 25%-50% in three, and more than 50% in five. Treatment in 11 patients with bilobar disease was accomplished via single infusions in six cases and sequential unilobar infusions in five patients. A single infusion was used to treat unilobar disease in the remaining patient. Median prescribed dose was 39.6 mCi (mean, 37.2 mCi; range, 17-67.5 mCi); the prescribed dose exceeded the delivered dose in six infusions (35%) as a result of embolic arterial occlusion. Radiologic response was stable in five of nine patients. Carcinoembryonic antigen levels decreased in four of seven patients. Four patients received chemotherapy concomitantly or after completion of treatment. Gastric ulceration in one patient was managed nonoperatively. Median survival times from diagnosis and treatment were 24.6 and 4.5 months, respectively. CONCLUSIONS Treatment with SIR-Spheres induces responses in patients with advanced unresectable colorectal hepatic metastases after multiple chemotherapy regimens. Inability to deliver the prescribed dose is related to the embolic effect of SIR-Spheres.

Pretransplant positive positron emission tomography/gallium scans predict poor outcome in patients with recurrent/refractory Hodgkin lymphoma.

The objective was to determine the prognostic value of functional imaging (FI) in predicting outcome of patients with recurrent/refractory Hodgkin lymphoma (HL) before undergoing high‐dose chemotherapy with autologous stem cell transplantation (ASCT).

Use of the Tyrosine Kinase Inhibitor Sunitinib in a Patient with von Hippel-Lindau Disease : Targeting Angiogenic Factors in Pheochromocytoma and Other von Hippel-Lindau Disease-Related Tumors

CONTEXT von Hippel-Lindau disease is characterized by highly vascularized tumors of multiple organs. EVIDENCE ACQUISITION We present a patient with von Hippel-Lindau disease with multiple renal and pancreatic tumors and a malignant pheochromocytoma infiltrative of the sacrum and associated with lymph nodule metastases. The pheochromocytoma expressed high protein level of vascular endothelial growth factor and platelet-derived growth factor-beta receptor. The patient presented with a poor performance status, severe pelvic pain, weight loss, and manifestations of catecholamine excess. EVIDENCE SYNTHESIS Treatment against malignant pheochromocytoma with surgery, chemotherapy, or participation in clinical trials was not feasible because of the patients poor performance status, the presence of multiple tumors, and the extension of the pheochromocytoma into the bones. Patient was treated with sunitinib, a potent tyrosine kinase inhibitor of vascular endothelial growth factor, platelet-derived growth factor, RET, c-KIT, and FLT-3 receptors. Six months of treatment with sunitinib was associated with normalization of the patients performance status and blood pressure, absence of symptoms of catecholamine excess, weight gain, disappearance of pain, shrinkage of each of the tumors (50% in the largest renal tumor, 38% in the largest islet cell tumor, 21% in the pelvic malignant pheochromocytoma), and reduction of plasma normetanephrines and chromogranin A. CONCLUSION This study provides evidence that targeting tyrosine kinase receptors such as the vascular endothelial growth factor pathway and the platelet-derived growth factor-beta receptor may have value in the treatment of VHL-related tumors including pheochromocytoma.

Yttrium-90 Microsphere Radioembolotherapy of Hepatic Metastatic Neuroendocrine Carcinomas after Hepatic Arterial Embolization

Hepatic artery radioembolization was performed in a cohort of patients with unresectable neuroendocrine hepatic metastases who exhibited hepatic progression or toxicity despite technically adequate embolization procedures without other reasonable therapeutic options. Eight patients (five men) with a median age of 55.5 years met the study criteria. Infusions of yttrium-90 resin microspheres were performed in a lobar fashion. Standard clinical, laboratory, and imaging follow-up was performed. Median hepatic parenchyma replacement by tumor was 55% (range, 25%-60%). Twelve (90)Y resin microsphere infusions were performed, and the median delivered activity was 33.25 mCi (range, 23-55 mCi). One partial response, four cases of disease stabilization, and three cases of progressive disease were noted. No cases of radiation-induced liver disease occurred. Median survival times were 14 months (range, 3-15 months) from the time of (90)Y microsphere treatment and 36.5 months (range, 16-105 months) from the time of diagnosis of hepatic metastases. In this cohort, (90)Y microsphere radioembolization of neuroendocrine hepatic metastases was not precluded by previous nonradioactive embolization procedures, but the effectiveness in this population requires further investigation.

Samarium lexidronam (153Sm-EDTMP): skeletal radiation for osteoblastic bone metastases and osteosarcoma

Radiation therapy can be an effective means to treat bone metastases, which occur in more than 50% of cancer patients. 153Samarium lexidronam (153Sm-EDTMP; Quadramet, Cytogen) is a radiopharmaceutical designed for deposition into bone metastases. Bone scans can identify patients that may benefit from targeted radiation therapy with 153Sm-EDTMP. As an unsealed source of radiation therapy, 153Sm-EDTMP is simple to administer: 1 mCi/kg is given in a similar fashion to a bone scan injection (99mTc-MDP bone scan injection is given at 0.2–0.35 mCi/kg. Therefore, both are administered intravenously. However, the radiation-absorbed dose and radiopharmaceutical energy are different). Nevertheless, despite simplicity of administration, 153Sm-EDTMP is underutilized for improving cancer pain in the skeleton. Repeated cycles and combined treatment with other modalities such as bisphosphonates, chemotherapy and/or external beam radiation are possible. 153Sm-EDTMP combined with bisphosphonates, chemotherapy and/or radiation may provide better palliation of bone metastases and also in bone-forming tumors (osteosarcoma). Encouraging experience using high-dose 153Sm-EDTMP for total marrow irradiation in hematologic malignancies involving the bones (e.g., myeloma or acute leukemia) is also reviewed.

Radioembolization of Yttrium-90 Microspheres for Hepatic Malignancy

The liver represents a frequent site for primary and secondary neoplasia. Cytoreductive techniques positively influence the outcome of disease progression in these patients. Transhepatic arterial radioembolotherapy utilizing yttrium-90 microspheres represents a recently available in situ therapy that has shown encouraging results in the treatment of these patients. Harnessing the skills of many different specialties, such as interventional radiology, surgical oncology, medical oncology, nuclear medicine, radiation oncology, medical physics, and radiation safety, brings invaluable expertise to the treatment process for a safe and effective radioembolization treatment program.

F-18 FDG positron emission tomographic image of an aortic aneurysmal thrombus.

A 70-year-old woman with a history of breast cancer was referred for an F-18 fluorodeoxyglucose (FDG)-positron emission tomographic (PET) scan to evaluate a 1.1-cm single pulmonary nodule detected on a computed tomographic (CT) scan to determine whether it was benign or malignant. An incidental finding on the PET scan was an aneurysm of the descending thoracic aorta. In addition, a well-defined crescent-shaped area of absent F-18 FDG uptake was apparent in the posterior mediastinum within the expected location of the lumen of the descending thoracic aorta and along its wall. A CT scan of the chest revealed an intraluminal thrombus in the aneurysm of the descending thoracic aorta corresponding in location to the photopenic area on the F-18 FDG-PET scan. The metabolically inert area on the F-18 FDG-PET scan was thought to represent a thrombus within the aortic aneurysm.

Tumor necrosis in osteosarcoma: inclusion of the point of greatest metabolic activity from F-18 FDG PET/CT in the histopathologic analysis

ObjectiveTo determine if the location of the point of maximum standardized uptake value (SUVmax) being included in or not included in the histopathologic slab section corresponded to tumor necrosis or survival.Materials and methodsTwenty-nine osteosarcoma patients underwent post-chemotherapy [fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) positron-emission tomography–computed tomography (PET/CT) prior to resection. PET/CT images were correlated with slab-section location as determined by photographs or knowledge of specimen processing. The location of the point of SUVmax was then assigned as being ‘in’ or ‘out’ of the slab section. Cox’s proportional hazard regression was used to evaluate relationships between the location and value of SUVmax and survival. Logistic regression was employed to evaluate tumor necrosis.ResultsNo correlation was found between the SUVmax location and survival or tumor necrosis. High SUVmax correlated to poor survival.ConclusionHigh SUVmax value correlated to poor survival. Minimal viable tumor (> 10%) following chemotherapy is a known indicator of poor survival. No correlation was found between the location of SUVmax and survival or tumor necrosis. Therefore, the SUVmax value either does not correspond to a sufficient number of tumor cells to influence tumor necrosis measurement or it was included in the out-of-slab samples that were directed to viable-appearing areas of the gross specimen. Since high SUVmax has been previously found to correspond to poor tumor necrosis, and tumor necrosis is simply an estimate of the amount of viable tumor, SUVmax likely represents many viable tumor cells. Therefore, when not in the slab section, SUVmax was likely included in the tumor necrosis measurement through directed sampling, validating our current method of osteosarcoma specimen analysis.

Radionuclide bone imaging in Erdheim-Chester disease

Erdheim-Chester disease is a rare sporadic systemic histiocytic disease of unknown etiology that routinely involves the diametaphyseal region of the long bones of the appendicular skeleton. In addition, there is frequent involvement of multiple internal organs producing protean manifestations. Although definitive diagnosis requires histopathologic confirmation, its appearance on bone scintigraphy is virtually pathognomonic of this entity. We report the case of a 53-year-old man with Erdheim-Chester disease who presented with lower extremity bone pain and was found to have the characteristic lesions of this condition on bone scintigraphy.