Abstract
Background/Aim: The diaphyses of long tubular bones are a very rare primary site of osteosarcomas and their characteristics and disease course are only poorly defined.
Patients and Methods: We screened the Cooperative Osteosarcoma Study Group’s (COSS) database for eligible cases and detected 162 (130 high-grade central, 3 low-grade central, 6 high-grade surface, 17 periosteal, 6 parosteal). Tumor characteristics, treatments, and outcomes were then investigated.
Results: Affected individuals were 86 males and 76 females, with a median age 16.0 (5.0-65.2) years). Tumors of the leg represented 88%, those of the femur alone 74%. Primary distant metastases affected 21% of patients. Treatments consisted of surgery (96%), radiotherapy (4%), and/or chemotherapy (97%). Tumor-response to neoadjuvant chemotherapy was good (<10% viable tumor) in 45% of 115 evaluable cases. After a median follow-up of 5.4 years, 5-year overall-/event-free survival expectancies were 75% and 57%, respectively. First events were mainly metastatic. By histology, five-year survival/event-free survival expectancies were 69%/52% for high-grade central and 100%/79% for periosteal osteosarcomas. The absence of primary metastases, no necessity to perform ablative surgery, a good response to preoperative chemotherapy, and achieving a macroscopic surgical remission were prognostically significant upon multivariate testing.
Conclusion: Diaphyseal and metaphyseal osteosarcomas share many characteristics. The former may, however, be associated with an increased rate of primary metastases and a lower response-rate to chemotherapy. Overall prognosis and prognostic factors seem comparable. Treatment strategies should follow those established for osteosarcoma.
Introduction
While rare, osteosarcoma still represents the most common primary bone-cancer. It mainly affects the metaphyses of long extremity bones. The distal femur is its most common primary location. The tumor has its peak incidence in adolescence, making an association with bone-growth likely (1). Given a high rate of metastatic spread, successful therapy requires combined local and systemic measures. Surgery along with neo-adjuvant and adjuvant chemotherapy can result in disease-free survival for most young patients (1, 2). The past decades, however, have not witnessed major prognostic improvements.
Diaphyses contribute far less to extremity-growth than do metaphyses. Hence, osteosarcomas situated to diaphyses are a rarity (3). As a consequence, limited data on tumors having arisen in this specific location is available.
We used the large database of the Cooperative Osteosarcoma Study Group (COSS) (4) to investigate patients with diaphyseal osteosarcomas in detail. We scrutinized affected individuals for demographic factors and prior history, tumor-characteristics, treatments received, and outcomes. It was thus aimed to characterize the site-specific features. The results obtained may now serve as a baseline for osteosarcomas arising in this unusual location and assist in dealing with such tumors.
Patients and Methods
Patient selection and data collection. The COSS-database 1980-20/09/2015 was screened for osteosarcomas of the diaphysis of femur, tibia, fibula, humerus, radius, or ulna. Follow-up was until December 31, 2023, or last patient contact. Recruitment and treatment strategies have been comprehensively reviewed (4-7). In brief, case-histories, personal characteristics, and tumor features as well as data on tumor treatment and patient follow-up were collected prospectively (5). Further information was gathered retrospectively from status-report forms, radiology-, pathology-, and surgery-reports, and progress-letters. The diagnosis of osteosarcoma required histological confirmation, reference-pathology being encouraged.
Guidance for local and systemic staging was provided, with only limited changes over time. In brief, all protocols included recommendations on investigation of the primary tumor site by X-rays, magnetic resonance imaging (MRI), computed tomography (CT) to be utilized if MRI not available, and a bone-scan. Metastatic spread was visualized by X-rays, chest-CT, and bone-scan. Other investigations were left to local decisions.
Recommendations for front-line therapy included both pre- and postoperative chemotherapy. Drugs varied but were generally doxorubicin, high-dose methotrexate (with limitations according to advancing patient-age), and cisplatin. Ifosfamide was used in selected protocols only. Other agents were rarely administered (4-7).
Local therapy included an attempt at complete surgery of all known tumor-sites. Wide margins according to Enneking (8) were attempted. The histologic response to pre-operative chemotherapy was graded according to Salzer-Kuntschik (9). Follow-up for tumor-recurrences was indefinite.
Survival analyses were performed starting at the date of the diagnostic procedure (biopsy or primary tumor-resection). Follow-up was until date last known to be alive or death, whichever appropriate. Secondary malignancies were noted but not counted as events.
Ethical Review Committee statement. All protocols were performed in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki) and approved by the appropriate ethics committee (Ethik-Kommission bei der Ärztekammer Hamburg nos. 500, 1147; Ethikkommission der Ärztekammer Westfalen-Lippe und der Westfälischen-Wilhelms Universität nos. 182/98 Biel2, 4IV Bie 2, 4 I Bielack, 5 V. Bielack; and Ethik-Kommission an der Medizinischen Fakultät der Eberhard-Karls-Universität und am Universitätsklinikum Tübingen no. 5 V Bielack). Informed consent was required from patients and/or legal guardians, whichever appropriate. The work was performed at Klinikum Stuttgart - Olgahospital.
Statistical analyses. The Kaplan–Meier method with 95%-confidence interval (CI) estimates was used for all survival analyses (10). Comparisons of survival expectancies between unrelated cohorts were made using the log-rank test (11). p-Values <0.05 were considered significant, no correction for multiple testing was made. Statistical analyses were carried out using the SPSS statistical software (IBM Corp. Released 2022. IBM SPSS Statistics for Windows, SPSS version 29.0.0.0., Armonk, NY, USA).
Results
Patients. In total, 192 patients with tumors of the diaphyses were registered. Upon review, 30 of these had to be excluded: Nineteen were found to have other histologies (undifferentiated pleomorphic sarcoma 12, leiomyosarcoma of the bone two, dedifferentiated chondrosarcoma two, Ewing sarcoma (initially misdiagnosed) two, fibrous dysplasia one). Eleven tumors were only entered upon relapse [nine after osteosarcoma-treatment, two after an erroneous diagnosis (osteoblastoma, chondromyxoid fibroma)].
The remaining 162 patients were eligible for all subsequent analyses. One-hundred and ten of these were from 46 pediatric, 42 from 26 medical, and 10 from three orthopedic institutions in Germany (129), Switzerland (17), Austria (14), or Hungary (2).
Patient and tumor-characteristics and tumor-treatments are summarized Table I. In brief, there were 86 (53%) males and 76 (47%) females. Their median age at diagnosis was 16.0 (range=5.0-65.2) years. Genetical tumor-predispositions were documented in 3/162 (2%) cases (Li-Fraumeni syndrome, Diamond-Blackfan anemia, STEAP-9 syndrome). In addition, one individual each was reported with alpha-1-antitrypsin deficiency and Asperger’s syndrome.
Clinical characteristics of osteosarcomas of the diaphysis, both in the whole cohort of 162 patients and divided by histological subgroups.
Six out of 162 (4%) patients had a history of having suffered a previous cancer. These were four rhabdomyosarcomas (RMS) (gluteal embryonal RMS at the age of 2.0 years treated with surgery, radiotherapy, and chemotherapy, followed by tibial high-grade central osteosarcoma at the age of 8.3 years; embryonal RMS of the thigh at the age of 2.8 ears treated with surgery, radiotherapy, and chemotherapy and then femoral high-grade central osteosarcoma at the age of 13.4 years in a patient with Li-Fraumeni’s syndrome; embryonal RMS of the thoracic wall at the age of 1.7 years treated with surgery and radiotherapy, then femoral periosteal osteosarcoma of at the age of 10.5 years in a patient with STEAP-9 syndrome, alveolar RMS of the right vastus lateralis at the age of 7.6 years treated with radiotherapy and chemotherapy, then femoral high-grade central osteosarcoma at the age of 16.0 years); a retinoblastoma at the age 1.1 of years (treated with surgery, then femoral high-grade central osteosarcoma at the age of 15.3 years), and a uterine carcinoma at the age of 41.3 years (treated with surgery and radiotherapy, then femoral low-grade central osteosarcoma at the age of 41.9 years).
Histologically, 130 (80%) osteosarcomas were classified as high-grade central, three (2%) as low-grade central, six (4%) as high-grade surface, 17 (11%) as periosteal, and six (4%) as parosteal tumors. Reference pathology was available for 124/162 (77%) of these. Among the 130 high-grade central osteosarcomas, information on histological subtyping was provided for 99 (76%) tumors and was osteoblastic [59 (59%)], chondroblastic [14 (14%)], fibroblastic or teleangiectatic [seven (7%), each], small-cell [four (4%)], giant-cell rich [three (3%)], and chondroblastoma-like [one (1%)]. Six (4%) tumors represented secondary malignancies.
The duration of symptoms prior to diagnosis was reported for 111/162 (69%) cases. Its median was 66 (range=0-1,280) days. A pathological fracture developed in 29/162 (18%) tumors (25 before, four during chemotherapy).
As for primary sites, 143 (88%) tumors were located in a leg [femur 119 (74%), tibia 21 (13%), fibula three (2%)] and 19 (12%) in an arm [humerus 16 (10%), radius two (1%), ulna one (<1%)]. The size of the osteosarcoma in relation to the affected bone was reported for 121/162 (75%) tumors and was less than one third in 47/121 (39%).
Metastases at diagnosis were detected in 34/161 (21%) cases (one no data). Metastases affected the lungs in 33/34 (97%) cases (two with additional spread to lymph-nodes) and were purely osseous in a single patient.
Chemotherapy was employed in 155/160 (97%) patients (two no data), of which 150/155 (97%) had appropriate information about timing. In these, chemotherapy was administered preoperatively only in 10 (7%), postoperatively only in 14 (9%), and pre- and postoperatively in 126 (84%) patients. Drugs administered were known for 151/155 (97%) tumors and included doxorubicin [148 (96%)], high-dose methotrexate [137 (88%)], cisplatin [136 (88%)], and ifosfamide [80 (52%)]. Thirty-three patients additionally received a variety of other agents (actinomycin D, bleomycin, etoposide (14 each), carboplatin (seven), liposomal muramyl-tripeptide (three), gemcitabine, vincristine (two each), cyclophosphamide, docetaxel, pazopanib, cabozantinib, sorafenib, everolimus, and interferon-α (one each) (multiple mentions possible).
One hundred and fifty-five/161 (96%) patients had tumor-surgery by limb-salvage procedures [115/155 (74%)] or ablative procedures [40/155 (26%; 26 amputations, 14 rotation-plasties)] (one no data on type of surgery). Tumor-response to preoperative chemotherapy was known for 115/142 osteosarcomas operated upon following pre-operative chemotherapy (27 no response-data). In these, it was good in 52/115 (45%) and poor in 63/115 (55%). Six out of 162 (4%) patients received radiotherapy (five in addition to surgery, one as definitive local therapy).
As a result of therapy, 147/161 (91%) individuals achieved a macroscopically complete surgical remission of all tumor-sites. Of the remaining 14 patients, 11 had had primary metastases, one received radiotherapy instead of tumor-surgery, and two were still within their preoperative treatment-period when their follow-up ended.
The median follow-up for all 162 patients was 5.4 (range=0.05-37.7) years. During this follow-up, three patients suffered unrelated malignancies, none with cancer prior to osteosarcoma: One developed urothelial carcinoma at the age of 33.4 years (following high-grade central osteosarcoma of the femur at the age of 15.2 years), one developed cutaneous squamous cell carcinoma of an unreported site at the age of 35.8 years (following high-grade central osteosarcoma of the tibia at the age of 14.2 years), the third developed breast-cancer at the age of 56.6 years (following high-grade surface osteosarcoma adjacent to the fibula at the age of 52.7 years).
Median follow-up for events was 3.4 (0.003-37.7) years. It was 7.6 (0.2-37.7) years for 95 patients remaining event-free and 1.2 (0.003-14.1) years for 67 patients with events. First events were osteosarcoma-related in 63 individuals [16 failures to achieve remission, 47 osteosarcoma-recurrences (42 metastatic, three isolated local, two combinations)], and four non-osteosarcoma-related (three deaths of an unrelated and one of an unknown cause). In the 44 patients who suffered metastases, these affected the lungs in all but five, which were purely osseous. In total, bony spread was present in nine individuals. Metastases to other sites were detected in three patients, all in addition to combined pulmonary and osseous recurrences.
The median follow-up period for 122 survivors was 7.4 (0.05-37.7) years: eight were alive without having ever achieved a surgical remission (five within the 1st year after diagnosis), four with active recurrences, and 110 in remission (95 1st, 10 2nd, three 3rd, two 4th).
Forty patients died after a median follow-up of 2.5 years (range=0.3-9.6 years). The causes of death included osteosarcoma in 33 patients (seven without achieving remission and 26 due to tumor recurrence: 15 after the first, six after the second, four after the third, and one after the fourth recurrence), treatment-related complications in five patients (three from sepsis during first-line therapy, one from a stroke, and one from secondary breast cancer), and unknown causes in two patients (one during first remission and 1 during first recurrence). Overall- and event-free survival probabilities are presented in Figure 1. Table II details these for all patients as well as for the most frequent subtypes, high-grade central and periosteal osteosarcoma. For the total cohort of 162 patients, the following variables were associated with statistically superior overall-survival outcomes at p<0.05: female sex (p=0.037), history of another malignancy (p=0.026), no pathological fracture (p=0.019), absence of primary metastases (p<0.001), limb-sparing surgery (p<0.001), macroscopically complete surgical remission (p<0.001). For event-free survival, these factors were tumor-size <1/3 of the involved bone (p=0.038), absence of primary metastases (p<0.001), limb-sparing surgery (p<0.001), good tumor response to preoperative chemotherapy (p=0.029). The extent of surgery was not assessable here, as incomplete surgery was counted as an event by definition.
Overall- (solid line) and event-free (dashed line) survival probabilities for (A) 130 patients with high-grade central osteosarcoma and (B) for 17 patients with periosteal osteosarcoma of the diaphysis.
Outcome of patients with osteosarcoma of the diaphysis 5 years after diagnosis, both for the total cohort of 162 patients and for the subgroups with conventional and periosteal tumors.
For 130 high-grade central osteosarcomas and overall-survival, absence of primary metastases (p<0.001), limb-sparing surgery (p=0.006), and achieving a macroscopically complete surgical remission (p<0.001) were statistically significant. For event-free survival, absence of primary metastases (p<0.001), limb-sparing surgery (p=0.007), and a good response to preoperative chemotherapy (p=0.029) were significant. Appropriate tests for overall-survival after periosteal osteosarcoma could not be performed as all 17 patients survived. No factor was found significant for event-free survival.
Multivariate models of event-free and overall-survival, including information on histologic response and (due to a considerable amount of missing data) excluding this variable, are presented in Table III. The presence of primary metastases, surgery by methods other than limb-salvage, and no macroscopically complete remission were negatively prognostic in all models. When added to the equations, poor response to pre-operative chemotherapy was also found to correlate with inferior outcomes.
Results of multivariate analyses of overall- and event-free-survival, presented separately for the total cohort and without considering tumor -response to pre-operative chemotherapy.
Discussion
This series of 162 patients with osteosarcomas of the diaphysis represents a benchmark. Interestingly, such tumors may demonstrate relatively few genetic predispositions. Their rate of primary metastases may be somewhat higher and their response-rate to chemotherapy somewhat lower than those found in extremity-osteosarcomas in general. Still, these tumors seem to respond to the same treatment principles and to carry a prognosis similar to osteosarcomas of the metaphyses.
So far, published reports have generally been limited to considerably less than fifty patients (12, 13). This considerably larger series covers both local and systemic treatments. Reference pathology being performed in over three quarters of tumors adds validity. The median follow-up of over five years for all patients and seven years for survivors seems long enough to capture most osteosarcoma-related events.
Only few patients in the current report suffered from a known tumor-predisposition-syndrome. Only a single of them was diagnosed with Li-Fraumeni syndrome. Very likely, the osteosarcoma occurring after a previous retinoblastoma also had a genetic background, although this was not assessed. This rather low frequency of pre-dispositions is in contrast to osteosarcoma in general. There, potentially predisposing genomic germline-alterations are suspected in up to a quarter of cases (14). The true frequency of predisposing syndromes in our cohort may of course have been underreported. However, the rarity at which we were made aware of such cases suggests that diaphyseal osteosarcomas might be less frequently driven by defined genomic alterations than metaphyseal tumors.
In osteosarcoma, tumorigenesis may be favored by previous cancer-therapies, particularly radiotherapy (15, 16). In addition to the two patients with known genetic tumor predisposition-syndromes and prior cancers, we were only aware of four pre-irradiated patients: These suffered their osteosarcoma following a retinoblastoma (probably also genetically induced, but not tested), two rhabdomyosarcomas, and a carcinoma of the uterus.
This series was not limited to high-grade central osteosarcoma. It was open to the disease in general. Approximately 20% of primaries were then found to be not of high-grade central histology. With 17 such cases or just over 10% of the total, periosteal osteosarcomas were the most frequent of these. The diaphysis seems prone to this osteosarcoma-variant (3). Other variants were limited to very few cases each, precluding specific analyses. A diligent diagnostic workup seems advisable as histologic osteosarcoma-variants may require very distinct therapeutic approaches.
Among high-grade central osteosarcomas, the results of histological subtyping proved the osteoblastic variant to be the most frequent. This may have been expected. Small-cell osteosarcoma, easily confused with Ewing sarcoma, merely accounted for less than a handful of cases. This adds credibility to our series.
Osteosarcomas are characterized by a striking male predominance (1). This sex-distribution is best explained by their trend to arise in areas of the bone which are actively growing, males tending to grow more than females. Diaphyses, however, grow less than metaphases do. Indeed and accordingly, the distribution of sex witnessed only a very slight male predominance. Growth does indeed seem important in osteosarcoma-tumorigenesis.
With a median age of approximately 16 years, patients with diaphyseal osteosarcomas seem neither younger nor older than osteosarcoma-patients in general (1). It is well established that patients with variants such as low-grade central or parosteal osteosarcoma tend to be significantly older (3). This was also the case in this cohort.
Here, diaphyseal primaries tended to favor the same bones as their metaphyseal counterparts do. Hence, the femur was by far the most frequently affected bone, followed by the tibia. As a result, the leg was affected far more often than the arm. The duration of symptoms prior to diagnosis, approximately two months, was not different from that in osteosarcoma of the extremities in general (2). The diaphyses are considerably thinner in width than are metaphyses. They are thus more prone to fracture with tumor-growth (17). Indeed, pathologic fractures were documented for more than a fifth of our patients and most often occurring prior to diagnosis. We did not observe pathologic fractures with any non-high-grade central osteosarcoma variants.
The extent of diaphyseal osteosarcomas at the time of diagnosis was notable, with more than 60% occupying at least one third of the length of the affected bone. In our experience with extremity osteosarcomas in general, this is only the case for one third (2). It seems that a tumor with a greater distance from any joint is less prone to stress, covered by ample muscles and other soft-tissues, and thus may cause fewer signs and symptoms. Such a tumor may therefore go unnoticed, growing for a longer period in time and reaching considerable size before diagnosis.
The presence of overt primary distant metastases is an ominous sign in any osteosarcoma (1). Their frequency in the present cohort, present in more than one out of every four patients with high-grade central osteosarcomas, seems noticeable. Almost always, the lungs were affected. The frequency of primary spread of over 25% seems higher than the 10%-20% reported for osteosarcomas in general (1, 18). An explanation could be the paucity of symptoms, leading to later diagnosis and favoring not only local but also systemic tumor-progression. A diligent search for systemic spread certainly seems indicated. On a positive note, primary spread was exceedingly rare for most osteosarcoma variants.
Osteosarcoma treatment was well documented for most tumors and almost all patients received chemotherapy. The drugs administered, primarily doxorubicin, high-dose methotrexate, and cisplatin, augmented by ifosfamide in approximately half of all patients, reflect standard practices (1, 4). The same holds true for the period over which chemotherapy was administered to the individual patient. What does seem to differ to a certain extent is the response to preoperative chemotherapy: More than half of tumors evaluable for this variable responded poorly. In contrast, more than half of metaphyseal tumors tend to respond well (1, 4).
Local therapy was almost always by surgery. Limb-salvage procedures were chosen in two thirds of cases. The long time-period which this series spans, going back to the early 1980s when ablative procedures were still very much standard, explains their relatively high frequency. Nowadays, better imaging techniques with better delineation of a tumor`s extent tend to make the latter preferable. All in all, approximately 90% of our patients managed to achieve a macroscopically complete surgical remission. Not surprisingly, this was more often the case if tumors seemed localized and less frequent if primary metastases were detected.
We were able to follow patients for a median of over five years, survivors for over seven years. These periods can be considered long. With a median of only 1.2 years from tumor-diagnosis, events tended to manifest rather early. These events were usually osteosarcoma-related and most frequently metastatic. As in the general osteosarcoma-population (1, 18), metastases were bound to affect the lungs, some isolated or combined distant bony recurrences being noted. Local recurrences were limited to a handful, probably both due to the relatively high frequency of ablative surgery and a better operability of diaphyseal lesions compared to those located around a joint.
Like cancers preceding osteosarcoma, secondary malignancies arising thereafter were uncommon with only three such cases being reported. With all the caution of a retrospective analysis and risks of underreporting, these results may again suggest a relatively low risk of tumor predisposition underlying diaphyseal osteosarcomas.
We observed approximately three quarters of all patients to survive, a little less than 60% event-free, at five years. For the most frequent osteosarcoma-type, high-grade central osteosarcoma, the numbers are in the lower range of what is reported for osteosarcoma in general (1, 2). A somewhat poorer prognosis compared to metaphyseal tumors could be explained by the higher rate of primary metastases. Periosteal osteosarcomas demonstrated their slower growth-dynamics by an 100% overall-survival rate at five years. However, some late recurrences occurred even in this subgroup and their long-term outlook might therefore be worse. Too few patients suffered from the other osteosarcoma variants to make additional subgroup-analyses feasible.
Regarding multivariate analyses, we could identify the presence of primary metastases, surgery by methods other than limb-saving resection, a poor tumor-response to pre-operative chemotherapy, and failure to achieve a macroscopically complete remission to be of significantly negatively impact. This situation does not differ much from that observed in osteosarcoma in general (2). It seems that clinicians dealing with diaphyseal osteosarcomas can largely rely on what they have learned about the disease as a whole.
Conclusion
The results from this series may serve as a benchmark for diaphyseal osteosarcomas. They indicate that tumors only infrequently arise on a known genetic basis, have a higher tendency for primary spread, and may respond somewhat less favorably to chemotherapy than do osteosarcomas in general. The overall prognosis of diaphyseal osteosarcomas, however, and their prognostic and predictive factors seem to be as expected for the disease. A combination of adequate chemotherapy and adequate surgery should be offered to affected patients and may lead to cure.
Acknowledgements
The Authors thank all patients and, where appropriate, their legal guardians for their consent into data-capture and analysis as well as the staff of all participating institutions for their willingness to supply data.
Footnotes
Authors’ Contributions
Daniel Baumhoer: Data curation; Writing–review & editing; Stefan S. Bielack: Conceptualization; Data curation; Formal analysis; Investigation; Methodology; Project administration; Resources; Validation; Visualization; Writing–original draft; Writing–review & editing; Claudia Blattmann: Data curation; Funding acquisition; Resources; Software; Supervision; Writing–review & editing; Arndt Borkhardt: Data curation; Writing–review & editing; Tobias Feuchtinger: Data curation; Writing–review & editing; Godehard Friedel: Data curation; Writing–review & editing; Jendrik Hardes: Data curation; Writing–review & editing; Semi ben Harrabi: Data curation; Writing–review & editing; Wolf Hassenpflug: Data curation; Writing–review & editing; Stefanie Hecker-Nolting: Data curation; Investigation; Validation; Writing–review & editing; Leo Kager: Data curation; Writing–review & editing; Thekla von Kalle: Data curation; Writing–review & editing; Matthias Kevric: Data curation; Formal analysis; Writing–review & editing; Antonia Knoll: Data curation; Formal analysis; Writing–review & editing; Thomas Kühne: Data curation; Writing–review & editing; Benjamin Sorg: Data curation; Formal analysis; Writing–review & editing; Claudia Rossig: Data curation; Writing–review & editing; Mathias Werner: Data curation; Writing–review & editing; Reinhard Windhager: Data curation; Writing–review & editing.
Conflicts of Interest
Stefan S. Bielack reports consulting fees from MAP Biopharma; consulting fees from SERB SAS; consulting fees from Atheneum Partners GmbH; consulting fees from Medicys Healthcare Fieldwork Experts; and payment for expert testimony by Zschimmer & Schwarz Mohsdorf GmbH & Co. KG. Arndt Borkhardt reports Consulting Fees from Norgine Ltd.; Consulting Fees from Fennec Pharmaceuticals Ltd.; and Consulting Fees from KV Nordrhein. Stefanie Hecker-Nolting reports support for the present manuscript by Förderkreis krebskranke Kinder Stuttgart e.V.; Grants or contracts from Deutsche Kinderkrebsstiftung, Bonn, Germany, and Leadership or fiduciary role in FOSTER (Fight Osteosarcoma through European Research), member of Executive Committee (EC), Lead WP3; COSS (Cooperative osteosarcoma study group), head of study group; and HIBISCUS, member of EC. Thekla von Kalle reports a leadership role for the German Speaking Pediatric Radiologists, GPR. Thomas Kühne reports participation on a Data Safety Monitoring Board or Advisory Board for Ipsen Innovation. Claudia Rossig reports Consulting Fees for Amgen; Consulting Fees for Novartis; Consulting Fees for Vertex Pharmaceuticals; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events for Amgen; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events for Novartis; Payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events for Vertex Pharmaceuticals; and support for attending meetings and/or travel by Amgen. Reinhard Windhager reports Consulting Fees for Johnson & Johnson Medical Limited; Consulting Fees for Stryker European Operations Limited; other financial or non-financial interests in De Puy Synthes Product Development by the Medical University of Vienna; other financial or non-financial interests in Johnson & Johnson Medical Limited Life Case Observation Agreement by the Medical University of Vienna; and other financial or non-financial interests in Johnson & Johnson Medical Limited Educational Agreement Med Uni by the Medical University of Vienna; Daniel Baumhoer, Claudia Blattmann, Tobias Feuchtinger, Godehard Friedel, Jendrik Hardes, Semi ben Harrabi, Wolf Hassenpflug, Leo Kager, Matthias Kevric, Antonia Knoll, Benjamin Sorg, and Mathias Werner report that they have no conflicts of interest.
Funding
The study was supported by Förderkreis krebskranke Kinder e. V., Stuttgart, Germany, and Gemeinsam für die Knochenkrebsforschung, Hamburg-Harburg, Germany.
Artificial Intelligence (AI) Disclosure
No artificial intelligence (AI) tools, including large language models or machine learning software, were used in the preparation, analysis, or presentation of this manuscript.
- Received July 18, 2025.
- Revision received August 1, 2025.
- Accepted August 5, 2025.
- Copyright © 2025 The Author(s). Published by the International Institute of Anticancer Research.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
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