Chemotherapy Regimens for Non-Metastatic Conventional Appendicular Osteosarcoma: A Literature Review Based on the Outcomes

Osteosarcoma is a rare condition with a complex treatment. Most protocols include neoadjuvant chemotherapy, surgery, and consolidation chemotherapy as the standard of treatment. However, the use of neoadjuvant chemotherapy lacks scientific evidence proving superiority in opposition to the use of isolated chemotherapy in an adjuvant regimen after surgery. We conducted a review for studies published in English between 1980 and 2020, using the MEDLINE/PubMed and Scopus electronic databases, to evaluate the outcomes when using neoadjuvant chemotherapy or adjuvant chemotherapy strategies in the treatment of non-metastatic appendicular osteosarcoma, as well as the toxicity associated with different chemotherapeutic regimens. Patients were divided into a neoadjuvant chemotherapy group (NAC) and adjuvant chemotherapy group (ACT), depending on the chemotherapy regimen used in association with surgery. A total of 1254 articles in English were screened by title and abstract, and 146 were pre-selected for full reading and analysis. A total of 24 assays matching the inclusion criteria were selected: 10 prospective and 14 retrospective studies. This review points to an absence of significative differences in outcomes, namely overall survival, disease-free survival/event-free survival rates, or toxicity, regarding neoadjuvant or single adjuvant chemotherapy strategies used in the treatment of appendicular non-metastatic osteosarcomas. However, there is a significative difference in population dimensions between the NAC and the ACT groups. Additionally, clinical presentation, tumor localization, tumor volume, or histological type were not considered, with these variables presenting the potential to influence these results. Despite these limitations, our findings should allow a re-thinking of our current practice and promote new opportunities to optimize treatment, always looking towards better survival and lower complications rates.

[1]  Xiuqing Gong,et al.  Osteosarcoma: a review of current and future therapeutic approaches , 2021, BioMedical Engineering OnLine.

[2]  T. Beckingsale,et al.  Surgical Advances in Osteosarcoma , 2021, Cancers.

[3]  A. Morsy,et al.  Age and Tumor Location Predict Survival in Nonmetastatic Osteosarcoma in Upper Egypt , 2020, Journal of pediatric hematology/oncology.

[4]  Robin L. Jones,et al.  Bone sarcomas: ESMO-PaedCan-EURACAN Clinical Practice Guidelines for diagnosis, treatment and follow-up. , 2018, Annals of oncology : official journal of the European Society for Medical Oncology.

[5]  W. Bi,et al.  The multidisciplinary treatment of osteosarcoma of the proximal tibia: a retrospective study , 2018, BMC Musculoskeletal Disorders.

[6]  Sudeep Gupta,et al.  Outcomes in non-metastatic treatment naive extremity osteosarcoma patients treated with a novel non-high dosemethotrexate-based, dose-dense combination chemotherapy regimen 'OGS-12'. , 2017, European journal of cancer.

[7]  L. Mirabello,et al.  Germline and somatic genetics of osteosarcoma — connecting aetiology, biology and therapy , 2017, Nature Reviews Endocrinology.

[8]  K. S. Hall,et al.  Comparison of MAPIE versus MAP in patients with a poor response to preoperative chemotherapy for newly diagnosed high-grade osteosarcoma (EURAMOS-1): an open-label, international, randomised controlled trial , 2016, The Lancet. Oncology.

[9]  P. Meltzer,et al.  Osteosarcoma: Current Treatment and a Collaborative Pathway to Success. , 2015, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[10]  K. S. Hall,et al.  EURAMOS-1, an international randomised study for osteosarcoma: results from pre-randomisation treatment† , 2014, Annals of oncology : official journal of the European Society for Medical Oncology.

[11]  R. Cozza,et al.  Nonmetastatic osteosarcoma of the extremity. Neoadjuvant chemotherapy with methotrexate, cisplatin, doxorubicin and ifosfamide. An Italian Sarcoma Group study (ISG/OS-Oss) , 2014, Tumori.

[12]  Ming Xu,et al.  Clinical analysis of osteosarcoma patients treated with high-dose methotrexate-free neoadjuvant chemotherapy. , 2014, Current oncology.

[13]  I. Lewis,et al.  Osteosarcoma treatment - where do we stand? A state of the art review. , 2014, Cancer treatment reviews.

[14]  H. Yoshikawa,et al.  Neoadjuvant and adjuvant chemotherapy with high-dose ifosfamide, doxorubicin, cisplatin and high-dose methotrexate in non-metastatic osteosarcoma of the extremities: a phase II trial in Japan , 2013, Journal of chemotherapy.

[15]  L. Trani,et al.  Survival from high-grade localised extremity osteosarcoma: combined results and prognostic factors from three European Osteosarcoma Intergroup randomised controlled trials. , 2012, Annals of oncology : official journal of the European Society for Medical Oncology.

[16]  Yanjun Zeng,et al.  Chemotherapy Response Analysis for Osteosarcom with Intra-arterial Chemotherapy by Subcutaneous Implantable Delivery System , 2011, Pathology & Oncology Research.

[17]  J. Roh,et al.  Comparison of Long-Term Outcome between Doublet and Triplet Neoadjuvant Chemotherapy in Non-Metastatic Osteosarcoma of the Extremity , 2011, Oncology.

[18]  K. S. Hall,et al.  Results of the Scandinavian Sarcoma Group XIV protocol for classical osteosarcoma , 2011, Acta orthopaedica.

[19]  R. Grimer,et al.  Earlier diagnosis of bone and soft-tissue tumours. , 2010, The Journal of bone and joint surgery. British volume.

[20]  R. Gorlick,et al.  Osteosarcoma: a review of diagnosis, management, and treatment strategies. , 2010, Clinical advances in hematology & oncology : H&O.

[21]  Y. Iwamoto,et al.  Multiinstitutional phase II study of neoadjuvant chemotherapy for osteosarcoma (NECO study) in Japan: NECO-93J and NECO-95J , 2009, Journal of orthopaedic science : official journal of the Japanese Orthopaedic Association.

[22]  L. Mirabello,et al.  Osteosarcoma incidence and survival rates from 1973 to 2004 , 2009, Cancer.

[23]  P. Casali,et al.  Osteosarcoma: ESMO clinical recommendations for diagnosis, treatment and follow-up. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[24]  A. Atalar,et al.  A Phase II Study of Cisplatin, Ifosfamide and Epirubicin Combination Chemotherapy in Adults with Nonmetastatic and Extremity Osteosarcomas , 2008, Oncology.

[25]  M. van Glabbeke,et al.  Improvement in histologic response but not survival in osteosarcoma patients treated with intensified chemotherapy: a randomized phase III trial of the European Osteosarcoma Intergroup. , 2007, Journal of the National Cancer Institute.

[26]  A. Petrilli,et al.  Results of the Brazilian Osteosarcoma Treatment Group Studies III and IV: prognostic factors and impact on survival. , 2006, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[27]  Piero Picci,et al.  Adjuvant and neoadjuvant chemotherapy for osteosarcoma of the extremities: 27 year experience at Rizzoli Institute, Italy. , 2005, European journal of cancer.

[28]  S. Ferrari,et al.  Neoadjuvant chemotherapy with high-dose Ifosfamide, high-dose methotrexate, cisplatin, and doxorubicin for patients with localized osteosarcoma of the extremity: a joint study by the Italian and Scandinavian Sarcoma Groups. , 2005, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[29]  J. Cullen,et al.  Improved Survival in Primary Nonmetastatic Pediatric Osteosarcoma of the Extremity , 2005, Clinical orthopaedics and related research.

[30]  R. Grimer,et al.  Surgical options for children with osteosarcoma. , 2005, The Lancet. Oncology.

[31]  J. Biermann,et al.  Adjuvant therapy of osteosarcoma—A Phase II trial , 2004, Cancer.

[32]  M. Link,et al.  Presurgical chemotherapy compared with immediate surgery and adjuvant chemotherapy for nonmetastatic osteosarcoma: Pediatric Oncology Group Study POG-8651. , 2003, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[33]  S. Smeland,et al.  Scandinavian Sarcoma Group Osteosarcoma Study SSG VIII , 2003 .

[34]  R. Grimer,et al.  Comparison of the Outcome of Conventional Osteosarcoma at Two Specialist International Orthopaedic Oncology Centres , 2003, Sarcoma.

[35]  B. Fuchs,et al.  Etiology of osteosarcoma. , 2002, Clinical orthopaedics and related research.

[36]  G. Rosen,et al.  Survival, prognosis, and therapeutic response in osteogenic sarcoma. The memorial hospital experience , 1992, Cancer.

[37]  J. Shuster,et al.  The effect of adjuvant chemotherapy on relapse-free survival in patients with osteosarcoma of the extremity. , 1986, The New England journal of medicine.

[38]  E. Mindell,et al.  Adjuvant adriamycin and cisplatin in newly diagnosed, nonmetastatic osteosarcoma of the extremity. , 1986, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[39]  M. Mison,et al.  Osteosarcoma , 1985, The Lancet.

[40]  G. Rosen,et al.  Preoperative chemotherapy for osteogenic sarcoma: Selection of postoperative adjuvant chemotherapy based on the response of the primary tumor to preoperative chemotherapy , 1982, Cancer.

[41]  R. Marcove,et al.  Osteogenic sarcoma under the age of twenty-one. A review of one hundred and forty-five operative cases. , 1970, The Journal of bone and joint surgery. American volume.

[42]  W. Winkelmann,et al.  Osteosarcoma: the COSS experience. , 2009, Cancer treatment and research.

[43]  A. Giuliano,et al.  Adjuvant chemotherapy for osteosarcoma: a randomized prospective trial. , 1987, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.