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

Primary bone cancers are extremely rare neoplasms, accounting for less than 0.2% of all cancers. Primary bone cancers show wide clinical heterogeneity and, perhaps most importantly, are often curable. With current multimodality treatment, including multi-agent chemotherapy, approximately three quarters of all patients diagnosed with osteosarcoma are cured. Updates for 2007 include changes in recommendations for treating chondrosarcoma, Ewing's sarcoma, and osteosarcoma. For the most recent version of the guidelines, please visit NCCN.org

Download Full-text

Primary Occipital Ewing’s Sarcoma with Subsequent Spinal Seeding

Case Reports in Pediatrics ◽

10.1155/2017/1521407 ◽

2017 ◽

Vol 2017 ◽

pp. 1-4 ◽

Cited By ~ 1

Author(s):

Ali Alqahtani ◽

Roaa Amer ◽

Eman Bakhsh

Keyword(s):

Posterior Fossa ◽

Ewing’S Sarcoma ◽

Ewing's Sarcoma ◽

Bone Cancer ◽

Surgical Excision ◽

Good Prognosis ◽

Bone Lesions ◽

History Of ◽

Magnetic Resonance Imaging Mri ◽

Whole Spine

Ewing’s sarcoma is a primary bone cancer that mainly affects the long bones. This malignancy is particularly common in pediatric patients. Primary cranial involvement accounts for 1% of cases, with occipital involvement considered extremely rare. In this case study, primary occipital Ewing’s sarcoma with a posterior fossa mass and subsequent relapse resulting in spinal seeding is reported. A 3-year-old patient presented with a 1-year history of left-sided headaches, localized over the occipital bone with progressive torticollis. Computed tomography (CT) imaging showed a mass in the left posterior fossa compressing the brainstem. The patient then underwent surgical excision followed by adjuvant chemoradiation therapy. Two years later, the patient presented with severe lower back pain and urinary incontinence. Whole-spine magnetic resonance imaging (MRI) showed cerebrospinal fluid (CSF) seeding from the L5 to the S4 vertebrae. Primary cranial Ewing’s sarcoma is considered in the differential diagnosis of children with extra-axial posterior fossa mass associated with destructive permeative bone lesions. Although primary cranial Ewing’s sarcoma typically has good prognosis, our patient developed metastasis in the lower spine. Therefore, with CNS Ewing’s sarcoma, screening of the entire neural axis should be taken into consideration for early detection of CSF seeding metastasis in order to decrease the associated morbidity and mortality.

Download Full-text

Primary Bone Tumours of the Pelvis in Childhood—Ewing's Sarcoma of the Ilium, Pubis and Ischium. (Report of 30 cases) (Part I)

Australasian Radiology ◽

10.1111/j.1440-1673.1989.tb03312.x ◽

1989 ◽

Vol 33 (4) ◽

pp. 354-360 ◽

Cited By ~ 4

Author(s):

K. KOZLOWSKI ◽

J. CAMPBELL ◽

G. BELUFFI ◽

J.C. HOEFFEL ◽

L. MORRIS ◽

...

Keyword(s):

Ewing’S Sarcoma ◽

Ewing's Sarcoma ◽

Bone Tumours ◽

Primary Bone ◽

Primary Bone Tumours

Download Full-text

Experimental Therapies and Clinical Trials in Bone Sarcoma

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2010.0052 ◽

2010 ◽

Vol 8 (6) ◽

pp. 715-725 ◽

Cited By ~ 4

Author(s):

Rashmi Chugh

Keyword(s):

Clinical Trials ◽

Ewing’S Sarcoma ◽

Ewing's Sarcoma ◽

Bone Sarcoma ◽

Pediatric Malignancies ◽

Experimental Therapies ◽

Bone Sarcomas ◽

Made In

Sarcomas originating in the bone represent a challenge for physicians and patients. Because they constitute only 0.2% of all adult malignancies and 6% of pediatric malignancies, resources for studying this disease are often limited.1,2 Nonetheless, significant advancements have been made in the treatment of this disease, and there are ongoing efforts toward improvement. This article discusses recently completed and currently enrolling clinical trials for the 3 most common bone sarcomas: osteosarcoma, Ewing's sarcoma family tumors, and chondrosarcoma.

Download Full-text

Chemotherapy in the Management of Osteosarcoma and Ewing's Sarcoma

Journal of the National Comprehensive Cancer Network ◽

10.6004/jnccn.2007.0039 ◽

2007 ◽

Vol 5 (4) ◽

pp. 449-455 ◽

Cited By ~ 11

Author(s):

Scott M. Schuetze

Keyword(s):

Ewing’S Sarcoma ◽

Ewing's Sarcoma ◽

Disease Patient ◽

Bone Sarcoma ◽

The United States ◽

High Grade ◽

Medical Oncologists ◽

Bone Sarcomas ◽

Localized Disease ◽

Relapsed Disease

Sarcomas of bone are rare malignancies diagnosed in fewer than 3000 individuals yearly in the United States. Ewing's sarcoma and most osteosarcoma are high-grade neoplasms and account for approximately one half of bone sarcoma cases. Fewer than 20% of patients presenting with localized Ewing's sarcoma or osteosarcoma are cured with surgery alone. Current management typically involves collaboration among orthopedic oncologists, medical oncologists, musculoskeletal radiologists, sarcoma pathologists, and radiation oncologists. Modern multidisciplinary management of Ewing's sarcoma and osteosarcoma has improved the cure rate of patients with localized disease to more than 50%. Primary chemotherapy for high-grade bone sarcomas often involves intensive, multiagent regimens, and few secondary chemotherapy options are available to treat refractory or relapsed disease. Patient participation in clinical trials of novel therapies for Ewing's sarcoma and osteosarcoma should be strongly encouraged.

Download Full-text

A DNA methylation-based classifier for accurate molecular diagnosis of bone sarcomas.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.15_suppl.11034 ◽

2017 ◽

Vol 35 (15_suppl) ◽

pp. 11034-11034

Author(s):

Shengyang Wu ◽

Benjamin Thomas Cooper ◽

Fang Bu ◽

Christopher Bowman ◽

Keith Killian ◽

...

Keyword(s):

Dna Methylation ◽

Synovial Sarcoma ◽

Ewing’S Sarcoma ◽

Ewing's Sarcoma ◽

Clinical Sample ◽

Methylation Status ◽

Accurate Diagnosis ◽

Cpg Sites ◽

Bone Sarcomas ◽

Methylation Profiling

11034 Background: Bone sarcomas present a unique diagnostic challenge because of the considerable morphologic overlap between different entities. The choice of optimal treatment, however, is dependent upon accurate diagnosis. Genome-wide DNA methylation profiling has emerged as a new approach to aid in the diagnosis of brain tumors, with diagnostic accuracy exceeding standard histopathology. In this work we developed and validated a methylation based classifier to differentiate between osteosarcoma, Ewing’s sarcoma, and synovial sarcoma. Methods: DNA methylation status of 482,421 CpG sites in 15 osteosarcoma, 10 Ewing’s sarcoma, and 11 synovial sarcoma samples were measured using the Illumina HumanMethylation450 array. From this training set of 36 samples we developed a random forest classifier using the 400 most differentially methylated CpG sites (FDR q value < 0.001). This classifier was then validated on 10 synovial sarcoma samples from TCGA, 86 osteosarcoma samples from TARGET-OS, and 15 Ewing’s sarcoma from a recently published series (Huertas-Martinez et al., Cancer Letters 2016). Results: Methylation profiling revealed three distinct molecular clusters, each enriched with a single sarcoma subtype. Within the validation cohorts, all samples from TCGA were correctly classified as synovial sarcoma (10/10, sensitivity and specificity 100%). All but one sample from TARGET-OS were classified as osteosarcoma (85/86, sensitivity 98%, specificity 100%) and all but one sample from the Ewing’s sarcoma series was classified as Ewing’s sarcoma (14/15, sensitivity 93%, specificity 100%). The single misclassified osteosarcoma sample was classified as Ewing’s sarcoma, and was later determined to be a misdiagnosed Ewing’s sarcoma based on RNA-Seq demonstrating high EWRS1 and ETV1 expression. An additional clinical sample that was misdiagnosed as a synovial sarcoma by initial histolopathology, was accurately recognized as osteosarcoma by the methylation classifier. Conclusions: Osteosarcoma, Ewing’s sarcoma and synovial sarcoma have distinct epigenetic profiles. Our validated methylation-based classifier can be used to provide an accurate diagnosis when histological and standard techniques are inconclusive.

Download Full-text

A rare case of acute paraplegia: primary Ewing’s Sarcoma of dorsal spine

International Surgery Journal ◽

10.18203/2349-2902.isj20181460 ◽

2018 ◽

Vol 5 (5) ◽

pp. 1927

Author(s):

Yeshwant Kumar N. N. T. ◽

V. T. T. Rajan

Keyword(s):

Ewing’S Sarcoma ◽

Ewing's Sarcoma ◽

Postoperative Outcome ◽

Cord Compression ◽

Acute Onset ◽

Radical Excision ◽

Benign Condition ◽

Acute Paraplegia ◽

Primary Bone

Ewing's sarcoma is a primary bone malignancy with the highest incidence in the second decade of life. Although it mostly affects the metaphyseal region of long growing bones, involvement of spine is not very uncommon especially the sacrum. Non-sacral spinal Ewing's sarcoma is rarer and often mimics a benign condition before spreading extensively. They present with neurologic deficits due to spinal cord compression, but acute onset paraplegia has not been previously reported. A high index of clinical suspicion can clinch the diagnosis early in the course of the disease. A prompt intervention is required to keep neurological damage to a minimum, and a correct combination of surgery, chemotherapy, and radiotherapy is required for better long-term patient outcome. We report a 11-year-old female who presented with acute paraplegia and had an excellent postoperative outcome after radical excision of a C7-D2 Ewing's sarcoma.

Download Full-text

Survival and signals of response in advanced sarcoma patients enrolled on phase 1 trials in the era of precision oncology and novel immunotherapies.

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.11063 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 11063-11063

Author(s):

Shiraj Sen ◽

Kenneth R. Hess ◽

David S. Hong ◽

Gerald Steven Falchook ◽

Roberto Pestana ◽

...

Keyword(s):

Clinical Trials ◽

Soft Tissue ◽

Ewing’S Sarcoma ◽

Ewing's Sarcoma ◽

Phase 1 ◽

Phase 1 Trials ◽

Best Response ◽

Bone Sarcomas ◽

Us Fda ◽

Advanced Sarcoma

11063 Background: Few effective US FDA approved therapies exist for refractory, metastatic sarcomas. Many of these patients therefore enroll onto phase 1 clinical trials. Because tumor-specific outcomes are not always reported in less common cancers such as sarcomas, outcomes of sarcoma patients treated with novel immunotherapy and targeted therapy approaches remains unknown. Methods: We analyzed clinical and next generation sequencing data from all sarcoma patients treated on phase 1 trials at MD Anderson Cancer Center (MDACC) and performed logistic and Cox proportional hazards regression analyses to evaluate response rate (RR), median time to progression (mTTP), clinical benefit rate (CBR; defined as CR, PR, or SD > 6 months), and median overall survival (OS). Results: Among the 406 patients with advanced sarcomas (321 soft tissue sarcoma, 85 bone sarcomas) treated on phase 1 trials at MDACC from May 2006 to May 2018, median age was 53 (range 11-84), 48% were female, with a median 3 prior lines of therapy (range 0-9). The most commonly treated soft tissue sarcoma subtypes included leiomyosarcoma (n = 66; 16%), liposarcoma (n = 52; 13%), GIST (n = 44; 11%), UPS (n = 14; 3%), and synovial sarcoma (n = 11; 3%) and most commonly treated bone sarcomas included osteosarcoma (n = 34; 8%), chondrosarcoma (n = 28; 7%), and Ewing’s sarcoma (n = 25; 6%). RR was 7% (95% CI 5, 10), mTTP was 2.9 months (95%CI 2.6, 3.1), CBR was 24% (95% CI 20, 29), mOS was 17.2 months (95% CI 13.8, 20.8). 2 patients had a CR as best response, 1 chondrosarcoma patient treated with an anti-APO2L/Trail agent and 1 Ewing’s sarcoma patient treated with the combination of an IGF1R inhibitor plus mTOR inhibitor. 26 patients (6%) had a PR as best response using novel immunotherapies targeting PD1, PDL1 plus CCR4, CTLA4 plus KIT, and TLR7/8 and novel targeted therapies against TRK, LRRC15, cMET, mTOR, VEGF, MDM2, KIT/PDGFRA, and FGFR. Responses were seen across sarcoma subtypes - ASPS, UPS, myxoid sarcoma, liposarcoma, GIST, carcinosarcoma, clear cell sarcoma, embryonal rhabdomyosarcoma, epitheliod sarcoma, fibrious histiosarcoma, and Ewing’s sarcoma. Conclusions: Our analysis identifies a reasonable survival in heavily pretreated, metastatic refractory sarcoma patients with responses seen with novel targeted therapies and immunotherapies that are not yet US-FDA approved. Biomarker analysis is ongoing to help identify the subset of responders in our cohort. Advanced sarcoma patients should be considered for molecular profiling and early phase clinical trials.

Download Full-text

Comparison of MRI and Histopathology with regard to Intramedullary Extent of Disease in Bone Sarcomas

Sarcoma ◽

10.1155/2019/7385470 ◽

2019 ◽

Vol 2019 ◽

pp. 1-5 ◽

Cited By ~ 1

Author(s):

Ashish Gulia ◽

Ajay Puri ◽

T. S. Subi ◽

Srinath M. Gupta ◽

S. L. Juvekar ◽

...

Keyword(s):

Standard Deviation ◽

Correlation Analysis ◽

Limb Salvage ◽

Ewing’S Sarcoma ◽

Ewing's Sarcoma ◽

Salvage Surgery ◽

Limb Salvage Surgery ◽

Bone Sarcomas ◽

The Mean ◽

Extent Of Disease

In today’s era, limb salvage surgery is the procedure of choice and current standard of care in appropriately selected patients of bone sarcomas. For adequate oncologic clearance, preoperative evaluation of the extent of tumor is mandatory. The present study was done to compare measurements of bone sarcomas (osteosarcoma, Ewing’s sarcoma, and chondrosarcoma) as determined by magnetic resonance imaging (MRI) with the histopathological extent seen on resected specimens. We prospectively evaluated 100 consecutive patients with a diagnosis of bone sarcoma who underwent limb salvage surgery between May 2014 and December 2014. The maximum longitudinal (cranio-caudal) dimension of tumor on the noncontrast T1-WI sequence of MRI (irrespective of whether it was pre/postchemotherapy) was compared with the gross dimensions of the tumor on histopathology. The arithmetic mean difference, Wilcoxon signed-rank test, and Spearman’s correlation analysis were used to test the differences and correlation between groups. Mean tumor size on MRI based on the largest extent on MRI was 12.1 ± 4.85 cm (mean ± standard deviation), while it was 10.77 ± 4.6 cm (mean ± standard deviation) on histopathology. In 79 cases, MRI overestimated the extent of disease; the mean was 1.79 cm with a standard deviation of 1.56 cm. When the disease extent was underestimated on MRI (13 cases), the mean was 0.58 cm with a standard deviation of 0.43 cm. In 8 cases (osteosarcoma (7), Ewing’s sarcoma (1)), MRI measurement was equal to histopathology. The Spearman correlation analysis showed a high correlation of tumor length on histopathology with the MRI for all patients (R = 0.948, P<0.0001). We thus conclude that MRI is accurate in delineating the extent of bone sarcomas. A margin of 2 cm from the maximum tumor extent is adequate to ensure appropriate surgical resection.

Download Full-text

Primary Ewing’s Sarcoma of the Spine in a Two-Year-Old Boy

Case Reports in Orthopedics ◽

10.1155/2016/8027137 ◽

2016 ◽

Vol 2016 ◽

pp. 1-4

Author(s):

Ali J. Electricwala ◽

Jaffer T. Electricwala

Keyword(s):

Spinal Canal ◽

Ewing’S Sarcoma ◽

Ewing's Sarcoma ◽

Cauda Equina ◽

Bone Tumour ◽

Tracer Uptake ◽

Tumour Mass ◽

Gene Testing ◽

Bone Sarcomas ◽

Good Improvement

Ewing’s Sarcoma (ES) is a highly malignant bone tumour. It may involve any part of the skeleton but the most frequent parts are the ilium and diaphysis of femur and tibia (Alfeeli et al., 2005; Zhu et al., 2012). Primary ES of the spine is extremely rare (Yan et al., 2011). It accounts for only 3.5 to 14.9 percent of all primary bone sarcomas. The age of presentation ranges from 12 to 24 years (median 21 years) (Ferguson, 1999; Sharafuddin et al., 1992; Klimo Jr. et al., 2009). We report an unusual case of primary ES of the spine in a two-year-old boy, who presented to us with paraparesis and features of cauda equina syndrome. MRI scan showed a tumour mass arising from the pedicle of L4 vertebra invading the spinal canal. Tc-99 bone scan showed increased tracer uptake in L4 vertebra and normal tracer uptake elsewhere in the skeleton. After reaching the diagnosis of a space occupying lesion invading the lumber spinal canal, we performed a decompressive laminectomy and a biopsy was sent which confirmed the diagnosis of ES. Immunohistochemistry showed tumour cells staining positive for CD-99 (specific stain for ES). Gene testing showed an EWS-FLI 1 chimera. Surgery was followed by good improvement in motor signs. The child was then referred to a specialized oncotherapy centre for further treatment, radiation, and chemotherapy. To the best of our knowledge, we are the first to report primary ES of the spine at the age of two years.

Download Full-text