Pete Anderson

Insulin Growth Factor-Receptor (IGF-1R) Antibody Cixutumumab Combined with the mTOR Inhibitor Temsirolimus in Patients with Refractory Ewing's Sarcoma Family Tumors

Purpose: Temsirolimus was combined with cixutumumab, a fully human IgG1 monoclonal antibody directed at the insulin growth factor-1 receptor (IGF-1R). Experimental Design: Patients received cixutumumab, 6 mg/kg i.v. weekly, and temsirolimus, 25 to 37.5 mg i.v. weekly (4-week cycles), with restaging after 8 weeks. Median follow-up was 8.9 months. Results: Twenty patients [17 with Ewings sarcoma (EWS), 3 with desmoplastic small-round cell tumor (DSRCT)] were enrolled. Twelve patients (60%) were men with a median age of 24 years and six median prior systemic therapies in a metastatic setting. The most frequent toxicities were thrombocytopenia (85%), mucositis (80%), hypercholesterolemia (75%), hypertriglyceridemia (70%), and hyperglycemia (65%; mostly grade I–II). Seven of 20 patients (35%) achieved stable disease (SD) for more than 5 months or complete/partial (CR/PR) responses. Tumor regression of more than 20% (23%, 23%, 27%, 100%, 100%) occurred in five of 17 (29%) patients with EWS, and they remained on study for 8 to 27 months. One of six patients with EWS who previously developed resistance to a different IGF-1R inhibitor antibody achieved a CR. Four of the seven best responders developed grade III mucositis, myelosuppression, or hyperglycemia, which were controlled while maintaining drug dose. Conclusion: Cixutumumab combined with temsirolimus was well-tolerated and showed preliminary evidence of durable antitumor activity in heavily pretreated EWS family tumors. Clin Cancer Res; 18(9); 2625–31. ©2012 AACR.

Treatment with Sunitinib for Patients with Progressive Metastatic Pheochromocytomas and Sympathetic Paragangliomas

CONTEXTnPatients with progressive metastatic pheochromocytomas (PHEOs) or sympathetic paragangliomas (SPGLs) face a dismal prognosis. Current systemic therapies are limited.nnnOBJECTIVESnThe primary end point was progression-free survival determined by RECIST 1.1 criteria or positron emission tomography with [(18)F]fluorodeoxyglucose/computed tomography ([(18)F]FDG-PET/CT), in the absence of measurable soft tissue targets. Secondary endpoints were tumor response according to RECIST criteria version 1.1 or FDG uptake, blood pressure control, and safety.nnnDESIGNnWe conducted a retrospective review of medical records of patients with metastatic PHEO/SPGL treated with sunitinib from December 2007 through December 2011. An intention-to-treat analysis was performed.nnnPATIENTS AND SETTINGnSeventeen patients with progressive metastatic PHEO/SPGLs treated at the Institut Gustave-Roussy and MD Anderson Cancer Center.nnnINTERVENTIONSnPatients treated with sunitinib.nnnRESULTSnAccording to RECIST 1.1, eight patients experienced clinical benefit; three experienced partial response, and five had stable disease, including four with predominant skeletal metastases that showed a 30% or greater reduction in glucose uptake on [(18)F]FDG-PET/CT. Of 14 patients who had hypertension, six became normotensive and two discontinued antihypertensives. One patient treated with sunitinib and rapamycin experienced a durable benefit beyond 36 months. The median overall survival from the time sunitinib was initiated was 26.7 months with a progression-free survival of 4.1 months (95% confidence interval = 1.4-11.0). Most patients who experienced a clinical benefit were carriers of SDHB mutations.nnnCONCLUSIONnSunitinib is associated with tumor size reduction, decreased [(18)F]FDG-PET/CT uptake, disease stabilization, and hypertension improvement in some patients with progressive metastatic PHEO/PGL. Prospective multi-institutional clinical trials are needed to determine the true benefits of sunitinib.

Ewing’s Sarcoma: Standard and Experimental Treatment Options

Opinion statementEwing sarcoma family tumors (EWS), which include classic Ewing’s sarcoma in addition to primitive neuroectodermal tumor and Askin tumor, are the second most common variety of primary bone cancer to afflict adolescents and young adults. Multi-disciplinary care incorporating advances in diagnosis, surgery, chemotherapy, and radiation has substantially improved the survival rate of patients with localized Ewing sarcoma to nearly 70%. Unfortunately, those advances have not significantly changed the long-term outcome for those with metastatic or recurrent disease; 5-year survival remains less than 25%. This apparent therapeutic plateau exists despite extensive effort during the last four decades to optimize the efficacy of cytotoxic chemotherapy through combination of chemotherapies of mechanistically diverse action, dose-dense scheduling (provided as frequently as every 2 weeks), increased adjuvant treatment duration, and higher dosage per cycle (facilitated with parallel strides in supportive care incorporating growth factors). As has already occurred for malignancies such as breast or colon cancer, the “-omics-based” revolution has enhanced our understanding of the molecular changes responsible for Ewing’s tumor formation and identified a number of potential targets (such as IGF-1R or mTOR) amenable to biological therapy. It has also created both a challenge and an opportunity to develop predictive biomarkers capable of selecting patients most likely to benefit from targeted therapy. In this review, we discuss current standard-of-care for patients with Ewing’s sarcoma and highlight the most promising experimental therapies in early-phase clinical trials.

Targeted Morphoproteomic Profiling of Ewing's Sarcoma Treated with Insulin-Like Growth Factor 1 Receptor (IGF1R) Inhibitors: Response/Resistance Signatures

Background Insulin-like growth factor 1 receptor (IGF1R) targeted therapies have resulted in responses in a small number of patients with advanced metastatic Ewings sarcoma. We performed morphoproteomic profiling to better understand response/resistance mechanisms of Ewings sarcoma to IGF1R inhibitor-based therapy. Methodology/Principal Findings This pilot study assessed two patients with advanced Ewings sarcoma treated with IGF1R antibody alone followed by combined IGF1R inhibitor plus mammalian target of rapamycin (mTOR) inhibitor treatment once resistance to single-agent IGF1R inhibitor developed. Immunohistochemical probes were applied to detect p-mTOR (Ser2448), p-Akt (Ser473), p-ERK1/2 (Thr202/Tyr204), nestin, and p-STAT3 (Tyr 705) in the original and recurrent tumor. The initial remarkable radiographic responses to IGF1R-antibody therapy was followed by resistance and then response to combined IGF1R plus mTOR inhibitor therapy in both patients, and then resistance to the combination regimen in one patient. In patient 1, upregulation of p-Akt and p-mTOR in the tumor that relapsed after initial response to IGF1R antibody might explain the resistance that developed, and the subsequent response to combined IGF1R plus mTOR inhibitor therapy. In patient 2, upregulation of mTOR was seen in the primary tumor, perhaps explaining the initial response to the IGF1R and mTOR inhibitor combination, while the resistant tumor that emerged showed activation of the ERK pathway as well. Conclusion/Significance Morphoproteomic analysis revealed that the mTOR pathway was activated in these two patients with advanced Ewings sarcoma who showed response to combined IGF1R and mTOR inhibition, and the ERK pathway in the patient in whom resistance to this combination emerged. Our pilot results suggests that morphoproteomic assessment of signaling pathway activation in Ewings sarcoma merits further investigation as a guide to understanding response and resistance signatures.

Novel bone cancer drugs: investigational agents and control paradigms for primary bone sarcomas (Ewing's sarcoma and osteosarcoma).

Background: New investigational agents and chemotherapy regimens including cyclophosphamide + topotecan, temozolomide + irinotecan, and anti-IGF-1R antibodies in Ewings sarcoma (ES) and liposomal muramyltripeptide phosphatidylethanolamine (L-MTP-PE), aerosol therapy, and bone-specific agents in osteosarcoma (OS) may improve survival and/or quality of life on ‘continuation’ therapy. Objective: Review of investigational approaches and control paradigms for recurrent or metastatic primary bone tumors. Methods: Analyze temozolomide + irinotecan data and review in the context of other newer approaches including antiangiogenesis, anti-IGF-1R antibodies and bisphosphonates for ES. Review some current state-of-the-art approaches for OS including L-MTP-PE, anti-IGF-1R inhibition, aerosol therapies and bone specific agents. Results/conclusion: L-MTP-PE with chemotherapy in OS has been shown to improve survival; compassionate access is available for recurrence and/or metastases. Aerosol therapy (granulocyte–macrophage colony stimulating factor, cisplatin, gemcitabine) for lung metastases is a promising approach to reduce systemic toxicity. The bone-specific agents including denosumab (anti-receptor activator of NF-κB ligand antibody) and bisphosphonates may have benefit against giant cell tumor, ES and OS. Anti-IGF-1R antibody SCH717454 has preclinical activity in OS but best effectiveness will most likely be in combination with chemotherapy earlier in therapy. Both temozolomide + irinotecan and cyclophosphamide + topotecan combinations are very active in ES and are likely to be tested with anti-IGF-1R antibodies against ES.

Multimodality treatment of osteosarcoma: Radiation in a high-risk cohort

Chemotherapy during radiation and/or bone‐seeking radioisotope therapy (153‐samarium; 1 mCi/kg) during radiation may improve osteosarcoma cancer control.

Outpatient Chemotherapy Plus Radiotherapy in Sarcomas: Improving Cancer Control With Radiosensitizing Agents

BACKGROUNDnCancer control by radiotherapy (RT) can be improved with concurrent chemotherapy. Outpatient strategies for sarcomas that combine chemotherapy and RT are possible since supportive care and RT techniques have improved.nnnMETHODSnThe current status of non-anthracycline chemotherapy in combination with radiation for high-risk sarcoma is reviewed.nnnRESULTSnIfosfamide with mesna and newer activated ifosfamide agents (ZIO-201 and glufosfamide) have high potential to improve sarcoma cancer control. In Ewings sarcoma and osteosarcoma, high-dose ifosfamide with mesna (2.8 g/m2/day of each x 5 days; mesna day 6) can be safely given to outpatients using continuous infusion. Reducing ifosfamide nephrotoxicity and central nervous system side effects are discussed. Other outpatient radiosensitization regimens include gemcitabine (600-1000 mg/m2/dose IV over 1 hour weekly x 2-3 doses), temozolomide (75 mg/m2/daily x 3-6 weeks), or temozolomide (100 mg/m2/dose daily x 5) + irinotecan (10 mg/m2/dose daily x 5 x 2 weeks). In osteosarcoma with osteoblastic metastases on bone scan, samarium (1 mCi/kg; day 3 of RT) and gemcitabine (600 mg/m2 IV over 1 hour day 9 of RT) is a radiosensitization strategy. Future drugs for radiosensitization include beta-D-glucose targeted activated ifosfamide (glufosfamide) and sapacitabine, an oral nucleoside with in vitro activity against solid tumors including sarcomas.nnnCONCLUSIONSnThe potential to treat major causes of sarcoma treatment failure (local recurrence and distant metastases) with concurrent chemotherapy during radiation should be considered in high-grade sarcomas.

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.

Toxicity of hyperthermic intraperitoneal chemotherapy (HIPEC) in pediatric patients with sarcomatosis/carcinomatosis: Early experience and phase 1 results†

Intra‐abdominal metastasis is a rare form of tumor dissemination in children. Complete surgical resection is usually deemed impossible. Children are frequently offered palliative care only. We adopted an aggressive approach for these cases which includes removal of dozens to hundreds of tumor nodules followed by perfusion of the abdominal cavity with hyperthermic chemotherapy (HIPEC) with a curative intent.

Can anthracycline therapy for pediatric malignancies be less cardiotoxic

Anthracyclines have a central role in the treatment of cancer in pediatric patients but confer an increased risk of cardiac dysfunction. Several strategies have been employed to help reduce anthracycline-induced cardiotoxicity, including pretreating the patient with the iron chelator dexrazoxane and infusing the dose of anthracycline over a longer period. Much focus has also been placed on the development of methods that decrease the toxicity of parent compounds, specifically through the use of drug carriers such as liposomes, and on the development of new, potentially less toxic anthracycline derivatives, such as amrubicin and pixantrone. We provide a review of these strategies, focusing on studies in pediatric patients when available, and support the idea that anthracycline therapy can be less cardiotoxic in pediatric patients.