Ewing Sarcoma—Diagnosis, Treatment, Clinical Challenges and Future Perspectives
Abstract
:1. Introduction
2. Diagnosis
2.1. Imaging (by V. Vieth)
2.1.1. Diagnostic Workup—The Timeless Value of Plain Radiographs for Deciphering Bone Lesions
2.1.2. Local Tumor Assessment and Staging—“Trust in T1”
2.1.3. Therapeutic Assessment and Follow-Up
2.2. Biopsy (by E. de Álava, W. Hartmann, and V. Vieth)
2.2.1. How to Biopsy in EwS?
2.2.2. The Risk of Tumor Seeding along the Access Path of Biopsy
2.2.3. Biopsy—The Holy Tissue Grail
2.3. Pathological Diagnosis (by E. de Álava, T. G. Grünewald, and W. Hartmann)
2.3.1. How to Diagnose EwS?
2.3.2. Historical Evolution of EwS and EwS-Related Entities
2.3.3. Round Cell Sarcoma with Non-ETS-Fusions and CIC/BCOR-Rearranged Sarcoma
3. Local Therapy
3.1. Operative Local Therapy (by S. Collaud, J. Hardes, and A. Streitbürger)
3.1.1. The Matter of Local Therapy—Scientifically Hard to Resolve, but Clinically Guided by Interdisciplinary Tumor Board Recommendations
3.1.2. Surgical Strategies—Both Form and Function Follow Local Control
3.1.3. Surgical Margins and Histopathological Response to Systemic Treatment—Implications for Additional Local Therapy
3.1.4. Initial Versus Chemotherapy Responsive Tumor—Operate to What Extent?
3.1.5. Pathological Fracture in EwS
3.1.6. EwS of the Extremities and the Role of Limb Perfusion
3.1.7. Pelvic and Sacral EwS—When and How to Operate?
3.1.8. Primary Thoracic EwS
3.1.9. Patients May Benefit from Early Referral—Even Prior Diagnostic Biopsy—But Do Not Benefit from Re-Resection or Debulking Strategies
3.1.10. Disseminated and Relapsed EwS
3.2. Radiotherapy (by B. Timmermann)
3.2.1. Role of RT and Timing
3.2.2. Modern RT Strategies and Techniques
3.2.3. Primary Tumor Site, Prescription Dose, and Target Volume Definition
3.2.4. RT for Relapse, Metastases and Whole-Lung Irradiation
3.2.5. Radiation Toxicity with High-Dose Treatment
3.2.6. Irradiation for Palliation
4. Systemic Therapy
4.1. Evolution of the Current Systemic Backbone for Classical EwS (by U. Dirksen, S. G. DuBois, and D. S. Shulman)
4.1.1. Development of VACA-Based Regimens—Multi-Agent Systemic Therapy Improves Outcomes
4.1.2. Addition of Ifosfamide and Etoposide Further Improves Outcomes
4.1.3. Intensified Therapies—Time but Not Dose or Duration Matters
4.1.4. Adding Conventional Agents to Existing Backbone Regimens Has Not Thus Far Improved Outcomes
4.2. Systemic Treatment of Relapsed Classical EwS Including Combination Therapies (by S. G. DuBois and D. S. Shulman)
4.2.1. Approach Relapse Therapy
4.2.2. Systemic Therapies for Relapsed Disease—Time to Relapse Dictates Novel Agents Versus Re-Challenge with Frontline Drugs
4.2.3. Maintenance Therapy in EwS
4.3. EwS-Targeted Therapy—Low-Hanging Fruit or Unfair Rumor? (by S. Bauer, U. Dirksen, S. G. DuBois, J. A. Toretsky, and D. S. Shulman)
4.3.1. Targeted Agents Will Be Necessary to Overcome the Limitations of Conventional Chemotherapy and to Reduce the Burden of Late Effects in EwS
4.3.2. Adding Targeted Therapies to Existing Backbone Regimens
4.3.3. Established and Emerging Targeted Therapies for Relapsed Disease
4.3.4. The FET-ETS Translocations—A Clear Target, with Both Direct and Indirect Strategies
4.3.5. Where Is Targeted Therapy Heading?
4.3.6. Challenges to Treat EwS in Low- and Middle-Income Countries
5. Scientific Perspectives on Clinical Enigmas of Disseminated EwS Disease
5.1. How Similar Are Primary Tumors with Metastatic Lesions? (by J. F. Amatruda and H. Kovar)
5.1.1. Clonal Evolution of Metastases Seeds in Intratumor Heterogeneity and Correlates with Mutational Burden
5.1.2. Lessons from Bulk Gene Expression Analyses Including Immune Contextures of EwS Tumors and in Peripheral Blood
5.2. How Immunogenic Are EwS Tumors and What Clinical Value Lies within? (by J. F. Amatruda and H. Kovar)
5.2.1. Prognostic Immune Contextures of EwS Tumors and in Peripheral Blood
5.2.2. Immunotargeting of EwS Tumors
5.3. Oncogene Plasticity—Myth or Tumor Strategy with Clinical Impact and Potential Therapeutic Consequence? (by J. F. Amatruda and H. Kovar)
EWSR1-FLI1 Oncogene Fluctuations as Metastatic Drivers in EwS
5.4. Why Does Outcome Differ between Lung Metastases and Metastases at Other Locations? (by J. F. Amatruda and H. Kovar)
5.4.1. Therapeutic Accessibility
5.4.2. Biological Concepts for Organotropism of EwS Metastasis
5.5. Are We on Track with Preclinical Models? (by J. F. Amatruda and H. Kovar)
5.5.1. Patient-Derived EwS Models
5.5.2. Non-Patient Derived EwS Models
5.5.3. “The” EwS Mouse Model—Chronically Unavailable (So Far)
6. Biomarkers
6.1. Status Report on Biomarkers in EwS (by E. de Álava, M. Metzler, and V. Vieth)
6.1.1. Diagnostic, Prognostic, and Therapeutic Markers in EwS
6.1.2. Limitations and Future Perspectives for EwS Biomarkers
7. Concluding Remarks (by Y. Uhlenbruch)
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
References
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Reference | Year of Publication | Chemotherapy Backbone Evaluated | Trial Name | Key Findings |
---|---|---|---|---|
[219] | 2003 | VDC vs. VDC/IE | INT-0091 | Five-year EFS improved from 54% to 69% with the addition of IE to VDC for patients with localized EwS |
[222] | 2003 | P6 (VDC/IE with augmented Cy) | MSK | Four-year EFS 82% for patients with localized EwS |
[105] | 2009 | VDC/IE with augmented alkylator dosing vs. standard VDC/IE | INT-0154 | No improvement in outcomes with alkylator dose intensification |
[223] | 2012 | IC-VDC/IE | AEWS0031 | Six-year EFS improved to 73% from 65% with interval compressed chemotherapy for localized EwS |
[7] | 2018 | VAI vs. VAI/HD-BuMel | Euro-E.W.I.N.G. 99 and Ewing 2008 | Eight-year EFS improved to 60.7% from 47.1% for localized high-risk EwS |
[229] | 2019 | VDC/IE vs. VDC/IE/VTC | AEWS1031 | No benefit to the addition of VCT cycles for localized EwS |
[232] | 2019 | VDC/IE vs. VDC/IE/ganitumab | AEWS1221 | No improvement in outcomes for metastatic EwS with the addition of ganitumab |
[6] | 2019 | VIDE induction + VAI/VAC (or VIA/HD-BuMel) vs. VDC/IE induction + IE/VC (or VAI/HD-BuMel) | EURO Ewing 2012 | VDC/IE induction was found on preliminary analysis to have superior PFS and OS compared to VIDE induction |
Reference | Year of Publication | Agents Evaluated | Key Findings |
---|---|---|---|
Trials of conventional chemotherapy for relapse | |||
[236] | 2009 | High-dose ifosfamide | High-dose ifosfamide is active in relapsed EwS previously treated with standard-dose ifosfamide |
[242] | 2006 | Topotecan/cyclophosphamide | 33% of patients with PR and 27% with SD |
[243] | 2000 | Topotecan/high-dose cyclophosphamide | Responses seen in patients with EwS |
[244] | 2004 | Irinotecan/temozolomide | Responses seen in patients with EwS |
[245] | 2009 | Irinotecan/temozolomide | 63% ORR |
[246] | 2012 | Gemcitabine/docetaxel | Limited activity seen in patients with EwS |
[238] | 2020 | High-dose ifosfamide vs. topotecan/cyclophosphamide vs. irinotecan/temozolomide vs. gemcitabine/docetaxel | High-dose ifosfamide and topotecan/cyclophosphamide arms superior to irinotecan/temozolomide and gemcitabine/docetaxel. Enrollment is ongoing. |
Trials of targeted therapies for relapse | |||
[250] | 2017 | Regorafenib (REGO) | 10% objective response rate and a median PFS of 3.6 months |
[251] | 2020 | Cabozantinib (CABONE) | 26% ORR |
[252] | 2010 | Figitumumab | 2/16 patients with PR |
[253] | 2011 | Figitumumab | 14% of patients with PR |
[254] | 2011 | R1507 | 10% ORR |
[255] | 2012 | Ganitumab | 6% ORR |
[256] | 2014 | Olaparib | No patients with objective response |
[257] | 2020 | Talazoparib/temozolomide | No patients with objective response, 15 with SD |
[258] | 2020 | Talazoparib/irinotecan +/− temozolomide | 73% of patients had a clinical response (1 CR; 4 PR; 11 SD) |
[259] | 2020 | TK216 | Two CR have been reported Enrollment is ongoing |
[260] | 2020 | Seclidemstat | Enrollment is ongoing |
Patient Cohort (Number of Patients) | Genes/Pathways/Cell Infiltration in Patient Tumors with Poor Prognosis | Reference | |
---|---|---|---|
Enriched | Downregulated | ||
Localized tumors– non-progression (n = 7) vs. progression (n = 7) |
|
| [314] |
Localized tumors – non-progression (n = 13) vs. progression (n = 17) additional 12 tumors for validation | ▪ MGST1 | [315] | |
Metastatic and localized tumors (n = 27)- non-regression (n = 7) vs. regression (n = 20) by chemotherapy |
| [316] | |
Primary tumors (n = 5) vs. unrelated metastasis samples (n = 6) | ▪ ICAM1 | [317] | |
Primary tumors (n = 56; additional n = 39 as validation cohort)– non-survivors vs. survivors |
| [318] | |
Primary tumors (n = 88; additional n = 57 as validation cohort)– relapse vs. relapse-free survival |
|
| [319] |
Primary tumors (n = 197)– non-survivors vs. survivors |
|
| [320] |
(Therapy naïve) Primary tumors (n = 27)– progression vs. non-progression |
| [321] |
Biomarker Characteristics | Patient Characteristics | Study Details | |||||
---|---|---|---|---|---|---|---|
Type | Category | Biomaterial | Number | Disease Status | Detection Rate (% Positive) | Conclusion | Reference |
EwS-specific biomarkers | |||||||
Circulating tumor cells | Diagnostic/ therapeutic | PB, BM | 16 | PB, BM at diagnosis (1 pts, 6 pts) BM during therapy (2 pts) | EwS cells in BM or PB can be identified by RT-PCR | [406] | |
Diagnostic/ therapeutic | PB, BM | 28 | Primary and recurrent | PB, BM in non-metastatic pts (25) PB, BM in metastatic/ relapsed pts (50) | RT-PCR could serve as a EwS-specific marker of residual disease during CTX | [407] | |
Diagnostic/ prognostic | Stem cell harvest; PB, BM | 11 | Stem cell harvest (100) | Number of cells may correlate with relapse after transplantation | [408] | ||
Circulating tumor RNA (ctRNA) | Diagnostic/ prognostic | PB | 28 | 68 | Detection preceded progression; specific transcript types may affect progression | [409] | |
Diagnostic/ prognostic | PB, BM | 26 | BM at diagnosis (43) PB, BM during follow up (58) | Occult tumor cells are strong predictors of recurrent disease in non-metastatic pts | [410] | ||
Diagnostic/ therapeutic | Tissue, PB | 10 | Tissue (83), PB (100) | EWSR1-FLI1 molecular diagnosis possible in PB even in absence of tissue; ctRNA correlated with 18F-FDG-PET parameters | [411] | ||
Circulating tumor cells + circulating tumor RNA | Diagnostic/ therapeutic | PB, BM, PBSC | 12 | Metastatic | PBSC (2.5) | RT-PCR signal declines in PB and BM during CTX | [412] |
Diagnostic | PB | 1 | [413] | ||||
Circulating tumor DNA (by EWSR1-FLI1 ctDNA PCR) | Diagnostic/ therapeutic | 1 | ddPCR to detect ctDNA could serve as a EwS-specific marker of recurrence | [397] | |||
Diagnostic/ therapeutic | PB | 20 | Localized and metastatic | Kinetics of EWSR1-FLI1 ctDNA correlated with tumor volume | [414] | ||
Diagnostic/ therapeutic | PB | 20 | 100 | Combination of 18F-FDG-PET/CT and ctDNA quantification could serve as a EwS-specific marker for CTX response and relapse | [415] | ||
Circulating tumor cells + ctDNA PCR | Diagnostic/ prognostic | PB, BM | Flow cytometry (109) PCR (225) | Flow cytometry (CD99(+), CD45(-)) (12.8) PCR (19.6) | Detection of micrometastatic disease by flow cytometry or RT-PCR is not associated with outcome | [416] | |
Circulating tumor DNA (by WGS) | Diagnostic | Tissue, PB | 11 | WGS (100) | ctDNA by both NGS and ddPCR could serve as a EwS-specific marker | [417] | |
Diagnostic/ therapeutic/ prognostic | PB | 11 | ctDNA levels corresponded to CTX response | [418] | |||
Diagnostic/ prognostic | PB | 94 | ctDNA in localized pts (53) | ctDNA detection associated with inferior outcomes | [419] | ||
Diagnostic | Tissue, PB | 2 | [420] | ||||
Circulating cell-free mitochondrial DNA (ccf mtDNA) | Diagnostic/ prognostic | PB | 25 | ccf mtDNA levels associated with metastatic disease | [421] | ||
MicroRNA– miR-125b | Diagnostic/ therapeutic | PB | 63 | miR-125b elevated in pts compared to healthy controls; miR-125b downregulation correlated with poor response to CTX | [422] | ||
MicroRNA– miR34a | Diagnostic/ therapeutic/ prognostic | PB | 31 | Localized and metastatic | High miR34a inversely correlated with tumor volume; miR34a elevated in localized compared to metastatic pts; miR34a increased in localized pts at diagnosis and after end of CTX | [423] | |
Extracellular vesicles (EV)– EwS-specific transcripts | Diagnostic | Preclinical model | EVs could serve as a EwS-specific marker | [424] | |||
Extracellular vesicles (EV)– EwS soluble EV proteome | Diagnostic/ prognostic | PB | 10 | Localized and metastatic | [425] | ||
EwS-non-specific biomarkers (cytokines and other secreted peptides) | |||||||
IGF-1 and IGF-BP3 | Prognostic | PB | 22 | Localized and metastatic | High baseline IGF-1 and IGF-BP3 associated with improved EFS; IGF-BP3 and IGF-2 increased during CTX | [426] | |
IL-6 and IL-8 | Diagnostic/ therapeutic/ prognostic | PB | 13 | Localized | [427] | ||
Diagnostic/ prognostic | Tissue, PB | 14 | IL-6 elevated in some pts with poor prognosis | [428] | |||
(Pro)cholecystokinin ((pro)CCK) | Diagnostic/ therapeutic/ prognostic | Tissue, PB | 12 | Primary and recurrent | ProCCK elevated in pts at primary Dx/ recurrence compared to pts during CTX; ProCCK correlated with tumor size | [429] | |
Pro-gastrin-releasing peptide (ProGRP) and neuron- specific enolase (NSE) | Diagnostic | Tissue, PB | 9 | ProGRP could serve as a EwS-specific marker | [430] | ||
Diagnostic/ prognostic | PB | 16 | ProGRP elevated in half of the pts; ProGRP reflected therapeutic response | [431] |
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Zöllner, S.K.; Amatruda, J.F.; Bauer, S.; Collaud, S.; de Álava, E.; DuBois, S.G.; Hardes, J.; Hartmann, W.; Kovar, H.; Metzler, M.; et al. Ewing Sarcoma—Diagnosis, Treatment, Clinical Challenges and Future Perspectives. J. Clin. Med. 2021, 10, 1685. https://doi.org/10.3390/jcm10081685
Zöllner SK, Amatruda JF, Bauer S, Collaud S, de Álava E, DuBois SG, Hardes J, Hartmann W, Kovar H, Metzler M, et al. Ewing Sarcoma—Diagnosis, Treatment, Clinical Challenges and Future Perspectives. Journal of Clinical Medicine. 2021; 10(8):1685. https://doi.org/10.3390/jcm10081685
Chicago/Turabian StyleZöllner, Stefan K., James F. Amatruda, Sebastian Bauer, Stéphane Collaud, Enrique de Álava, Steven G. DuBois, Jendrik Hardes, Wolfgang Hartmann, Heinrich Kovar, Markus Metzler, and et al. 2021. "Ewing Sarcoma—Diagnosis, Treatment, Clinical Challenges and Future Perspectives" Journal of Clinical Medicine 10, no. 8: 1685. https://doi.org/10.3390/jcm10081685
APA StyleZöllner, S. K., Amatruda, J. F., Bauer, S., Collaud, S., de Álava, E., DuBois, S. G., Hardes, J., Hartmann, W., Kovar, H., Metzler, M., Shulman, D. S., Streitbürger, A., Timmermann, B., Toretsky, J. A., Uhlenbruch, Y., Vieth, V., Grünewald, T. G. P., & Dirksen, U. (2021). Ewing Sarcoma—Diagnosis, Treatment, Clinical Challenges and Future Perspectives. Journal of Clinical Medicine, 10(8), 1685. https://doi.org/10.3390/jcm10081685