Osteosarcoma is the bone tumor that most commonly affects children, adolescents, and young adults. Before 1970, treatment primarily included surgical resection. However, the introduction of ...chemotherapy led to a dramatic improvement in prognosis for patients with localized osteosarcoma; long-term survival rates of less than 20% improved to 65% to 70% after the advent of multiagent chemotherapy regimens. Controversy concerning the ideal combination of chemotherapy agents ensued throughout the last quarter of the 20th century because of conflicting and often nonrandomized data. However, large cooperative group studies and international collaboration have demonstrated that the most effective regimens include the combination of high-dose methotrexate, doxorubicin, and cisplatin (MAP). The introduction of biologic agents such as muramyl tripeptide and the use of additional cytotoxic chemotherapy such as ifosfamide have not definitively improved the survival of patients with osteosarcoma. Collaborative efforts to increase understanding of the biology of osteosarcoma and the use of preclinical models to test novel agents will be critical to identify the path toward improving outcomes for patients. Once promising agents are identified, an international infrastructure exists for clinical trials. Herein, biologic, preclinical, and clinical trial efforts will be described along with future international collaborative strategies to improve outcomes for patients who develop this challenging tumor.
Introduction
Craniofacial bones may be the site of origin of various sarcomas. We review the various malignancies affecting this region of the body and attempt to put systemic treatment approaches ...into perspective.
Material and methods
Non-systematic literature review
Results
Conventional types of osteosarcoma, Ewing sarcoma, and chondrosarcoma are the most frequent bone sarcomas occurring in craniofacial region, but variants may occur. The tumors’ biologies and the resulting treatment strategies vary distinctly. As a general rule, local control remains paramount regardless of histology. The efficacy of antineoplastic chemotherapy varies by type of malignancy. It is clearly indicated in Ewing sarcoma and related tumors, potentially of benefit in high-grade osteosarcoma, undifferentiated pleomorphic sarcoma, dedifferentiated and mesenchymal chondrosarcoma, and of no proven benefit in the others.
Conclusions
Various histologies demand various and distinct treatment approaches, with local control remaining paramount in all. The efficacy of systemic treatments varies by type of tumor. Prospective trials would help in all of these to better define systemic treatment strategies.
Osteosarcoma is the most common primary malignant tumour of the bone. Osteosarcoma incidence is bimodal, peaking at 18 and 60 years of age, and is slightly more common in males. The key ...pathophysiological mechanism involves several possible genetic drivers of disease linked to bone formation, causing malignant progression and metastasis. While there have been significant improvements in the outcome of patients with localized disease, with event-free survival outcomes exceeding 60%, in patients with metastatic disease, event-free survival outcomes remain poor at less than 30%. The suspicion of osteosarcoma based on radiographs still requires pathological evaluation of a bone biopsy specimen for definitive diagnosis and CT imaging of the chest should be performed to identify lung nodules. So far, population-based screening and surveillance strategies have not been implemented due to the rarity of osteosarcoma and the lack of reliable markers. Current screening focuses only on groups at high risk such as patients with genetic cancer predisposition syndromes. Management of osteosarcoma requires a multidisciplinary team of paediatric and medical oncologists, orthopaedic and general surgeons, pathologists, radiologists and specialist nurses. Survivors of osteosarcoma require specialized medical follow-up, as curative treatment consisting of chemotherapy and surgery has long-term adverse effects, which also affect the quality of life of patients. The development of osteosarcoma model systems and related research as well as the evaluation of new treatment approaches are ongoing to improve disease outcomes, especially for patients with metastases.
To determine demographic data and define prognostic factors for long-term outcome in patients presenting with high-grade osteosarcoma of bone with clinically detectable metastases at initial ...presentation.
Of 1,765 patients with newly diagnosed, previously untreated high-grade osteosarcomas of bone registered in the neoadjuvant Cooperative Osteosarcoma Study Group studies before 1999, 202 patients (11.4%) had proven metastases at diagnosis and therefore were enrolled onto an analysis of demographic-, tumor-, and treatment-related variables, response, and survival. The intended therapeutic strategy included pre- and postoperative multiagent chemotherapy as well as aggressive surgery of all resectable lesions.
With a median follow-up of 1.9 years (5.5 years for survivors), 60 patients were alive, 37 of whom were in continuously complete surgical remission. Actuarial overall survival rates at 5 and 10 (same value for 15) years were 29% (SE = 3%) and 24% (SE = 4%), respectively. In univariate analysis, survival was significantly correlated with patient age, site of the primary tumor, number and location of metastases, number of involved organ systems, histologic response of the primary tumor to preoperative chemotherapy, and completeness and time point of surgical resection of all tumor sites. However, after multivariate Cox regression analysis, only multiple metastases at diagnosis (relative hazard rate RHR = 2.3) and macroscopically incomplete surgical resection (RHR = 2.4) remained significantly associated with inferior outcomes.
The number of metastases at diagnosis and the completeness of surgical resection of all clinically detected tumor sites are of independent prognostic value in patients with proven primary metastatic osteosarcoma.
To evaluate the impact of patient, tumor, and treatment-related factors on outcome in unselected patients with recurrent osteosarcoma.
Five hundred seventy-six consecutive patients who had achieved a ...first complete surgical remission (CR) during combined-modality therapy on neoadjuvant Cooperative Osteosarcoma Study Group (COSS) protocols and then developed recurrent osteosarcoma were analyzed (median time from biopsy to relapse, 1.6 years; range, 0.1 to 14.3 years). There were 501 patients with metastases, 44 with local recurrences, and 31 with both. Metastases involved lungs (469 patients), bones (90 patients), and/or other sites (54 patients).
After a median follow-up of 1.2 years for all patients and 4.2 years for survivors, actuarial overall survival (OS) rates at 2, 5, and 10 years were 0.38, 0.23, and 0.18, respectively. Five-year OS was 0.39 for 339 patients with and 0.00 for 229 patients without a second surgical CR (P < .0001). A long time to relapse, a solitary lesion, and, in the case of pulmonary metastases, unilateral disease and the absence of pleural disruption, were of positive prognostic value in uni- and multivariate analyses, as were a second surgical CR and the use of second-line chemotherapy. Radiotherapy was associated with moderately prolonged survival in patients without a second CR. The very limited prognostic differences associated with the use of second-line chemotherapy appeared to be more pronounced with polychemotherapy.
Time to relapse and tumor burden correlate with postrelapse outcome in osteosarcoma. Complete surgery is an essential component of curative second-line therapy. Chemotherapy, particularly chemotherapy with more than one agent, may contribute to limited improvements in outcome.
To evaluate patient and tumor characteristics, treatment, and outcomes in a large cohort of unselected patients with second and subsequent recurrences of osteosarcoma.
Two hundred forty-nine ...consecutive patients who had originally received combined-modality therapy on neoadjuvant Cooperative Osteosarcoma Study Group protocols and went on to develop a total of 409 second and subsequent osteosarcoma recurrences were analyzed for patient-, tumor-, and treatment-related factors and outcomes.
Five-year overall and event-free survival rates were 16% and 9% for 249 second, 14% and 0% for 93 third, 13% and 6% for 38 fourth, and 18% and 0% for 14 fifth recurrences, respectively. The proportion of recurrences confined to the lungs decreased and the proportion of those with chest wall involvement increased with increasing numbers of recurrences. The duration of relapse-free intervals and the number of lesions at recurrence correlated with outcomes. While only one of 205 patients with rerecurrence survived past 5 years without surgical remission, 5-year overall and event-free survival rates were 32% and 18% for 119 second, 26% and 0% for 45 third, 28% and 13% for 20 fourth, and 53% and 0% for five fifth recurrences, respectively, in which a renewed surgical remission was achieved. The use of chemotherapy correlated with longer survival in patients without surgical remissions.
To our knowledge, this is the first report of survival estimates derived from large cohorts of unselected patients with second and subsequent osteosarcoma recurrences. It confirms the overwhelming importance of surgical clearance. Prognostic indicators after rerecurrences resemble those known from first recurrence. The exact role of re-treatment with chemotherapy, particularly in the adjuvant situation, remains to be defined.
Osteosarcoma, a bone cancer most commonly seen in adolescents and young adults, is usually a high-grade malignancy characterized by a very high risk for the development of pulmonary metastases. ...High-grade osteosarcomas are usually treated by preoperative and postoperative chemotherapy and surgery, with a very limited number of active agents available. Rarer lower-grade variants such as parosteal and periosteal osteosarcoma or low-grade central osteosarcoma are treated by surgery only. Imaging to search for possible metastases focuses on the lung. Computed tomography is the most sensitive method but cannot reliably distinguish small metastases from benign lesions. Advances of local imaging and surgical reconstruction now allow the use of limb-salvage in an ever-increasing proportion of patients. While still troubled by complications, non-invasive endoprosthesis-lengthening mechanisms have led to an increased uptake of limb-salvage, even for young, skeletally immature patients. Radiotherapy is employed when osteosarcomas cannot be removed with clear margins, but very high doses are required, and both proton and carbon-ion radiotherapy are under investigation. Unfortunately, the past 30 years have witnessed few, if any, survival improvements. Novel agents have not led to universally accepted changes of treatment standards. In patients with operable high-grade osteosarcomas, the extent of histological response to preoperative chemotherapy is a significant predictive factor for both local and systemic control. Attempts to improve prognosis by adapting postoperative treatment to response, recently tested in a randomized, prospective setting by the European and American Osteosarcoma Study Group, have not been proven to be beneficial. Many agree that only increased knowledge about osteosarcoma biology will lead to novel, effective treatment approaches and will be able to move the field forward.
Osteosarcoma, the most common type of primary malignant tumour that develops in bone, can be classified into several different sub-types. While the majority of osteosarcomas are highly malignant, ...there are some low-grade variants. Since the introduction of chemotherapy into the multi-modal treatment regimen of high-grade osteosarcoma, its prognosis has impressively improved, with long-term survival being achieved in two-thirds of all patients. This review summarises current chemotherapeutic treatment strategies in classical osteosarcoma and also addresses the indication for chemotherapy in more unusual types and variants. It emphasises the need for treatment in specialised centres and within prospective, multi-institutional trials, amongst which EURAMOS1 and EURO-B.O.S.S are currently active in many European countries.
Abstract The ‘Individualized Therapy for Relapsed Malignancies in Childhood’ (INFORM) precision medicine study is a nationwide German program for children with high-risk relapsed/refractory ...malignancies, which aims to identify therapeutic targets on an individualised basis. In a pilot phase, reported here, we developed the logistical and analytical pipelines necessary for rapid and comprehensive molecular profiling in a clinical setting. Fifty-seven patients from 20 centers were prospectively recruited. Malignancies investigated included sarcomas (n = 25), brain tumours (n = 23), and others (n = 9). Whole-exome, low-coverage whole-genome, and RNA sequencing were complemented with methylation and expression microarray analyses. Alterations were assessed for potential targetability according to a customised prioritisation algorithm and subsequently discussed in an interdisciplinary molecular tumour board. Next-generation sequencing data were generated for 52 patients, with the full analysis possible in 46 of 52. Turnaround time from sample receipt until first report averaged 28 d. Twenty-six patients (50%) harbored a potentially druggable alteration with a prioritisation score of ‘intermediate’ or higher (level 4 of 7). Common targets included receptor tyrosine kinases, phosphoinositide 3-kinase–mammalian target of rapamycin pathway, mitogen-activated protein kinase pathway, and cell cycle control. Ten patients received a targeted therapy based on these findings, with responses observed in some previously treatment-refractory tumours. Comparative primary relapse analysis revealed substantial tumour evolution as well as one case of unsuspected secondary malignancy, highlighting the importance of re-biopsy at relapse. This study demonstrates the feasibility of comprehensive, real-time molecular profiling for high-risk paediatric cancer patients. This extended proof-of-concept, with examples of treatment consequences, expands upon previous personalised oncology endeavors, and presents a model with considerable interest and practical relevance in the burgeoning era of personalised medicine.
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