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Purpose: Many publications address the epidemiology of secondary osteosarcomas following retinoblastoma. Treatment- and outcome-related information is, however, scarce. We used a large cooperative group’s database to study this issue. Patients and methods: The database Cooperative Osteosarcoma Study Group COSS was searched for patients with osteosarcoma following a previous retinoblastoma. Patients were then analyzed for demographic factors, local/systemic treatments received, and outcomes. Results: 28 eligible patients were identified. Median age at retinoblastoma was .5 years, 89% occurred bilaterally. Retinoblastoma-therapy was by surgery in 26/27, radiotherapy in 26/27, chemotherapy in 10/26 (rest unknown). Osteosarcoma was diagnosed after 13.7 (3.1 – 36.1) years, extremities and head/neck affected in 14/28, each. Four/28 patients had primary metastases. Osteosarcoma treatment included chemotherapy in all cases, local therapy surgery in 27/28. Histological response was good in 9/16 evaluable cases. Surgery of all sites was macroscopically complete in 23/27 operated tumors and microscopically complete in 17/26 (1 unknown). Radiotherapy was administered to 3 craniofacial tumors. Median follow-up was 3.5 (.4 – 30.1) years from osteosarcoma diagnosis, 8/28 patients remaining event-free. Altogether, five patients suffered further secondary malignancies. Actuarial overall and event-free survival at 2 and 5 years from osteosarcoma were 73% (standard error: 8%) / 50% (10%) and 47% (10%) / 22% (9%), respectively. Conclusion: This comparatively large cohort of osteosarcomas after retinoblastoma proves that the latter may be treated curatively. While their prognosis is far worse than that of primary osteosarcomas, partly due to a predilection for craniofacial involvement, selected patients may still become long-term survivors with appropriate therapies.

Abstract Purpose Prognostic factors have been well described for osteosarcoma, but analyses evaluating the further course of long‐term survivors are lacking. We used the large database of the Cooperative Osteosarcoma Study Group (COSS) to perform such an analysis. Patients and Methods The COSS database 1980‐04/2019 was searched for 5‐year survivors of primary high‐grade central osteosarcoma of the extremities or trunk. Identified patients were analyzed for their further survival outcomes, assessing potentially prognostic and predictive factors already evident at initial disease presentation and treatment as well as their disease course during the first 5 years of follow‐up. Results Two thousand and nine former eligible patients were identified (median age at initial diagnosis 15.1 (2.5–63.0) years; male vs. female 1149 (57.2%) vs. 860 (42.8%); extremities vs. trunk 1927 (95.9%) vs. 82 (4.1%); extremity primaries

Abstract Background To evaluate patient and tumour characteristics, treatment and their impact on survival in patients with a solitary pulmonary metastasis at first relapse of high‐grade osteosarcoma. Procedure Two‐hundred and nineteen consecutive patients who had achieved a complete surgical remission and then developed a solitary pulmonary metastasis at first recurrence of high‐grade osteosarcoma were retrospectively reviewed. Results Two hundred and three (94.9%) of 214 patients achieved a second complete remission. After a median time from initial diagnosis of osteosarcoma to first relapse of 2.3 years (range, 0.3–18.8 years), actuarial post‐relapse overall survival after 2 and 5 years was 72.0% and 51.2%. Post‐relapse event‐free survival was 39.1% and 31.1%. Median follow‐up time was 3.2 years (range, 0.1–29.4 years). A longer time until first relapse and diagnosis due to imaging were positive prognostic factors in uni‐ and multivariate analyses, as were a second complete surgical remission and, in regard to death, the absence of a subsequent relapse. The use of salvage chemotherapy and radiotherapy were not associated with patient outcomes, nor was the surgical approach (thoracoscopy vs. thoracotomy) nor the exploration (uni‐ vs. bilateral). Conclusion Approximately half of the patients who experience a solitary pulmonary relapse at first recurrence of osteosarcoma remain alive 5 years after this first relapse. Only one third will remain disease‐free. A complete surgical resection of the lesion is essential for long‐term survival while relapse chemotherapy does not seem to improve survival. Innovative therapies are required to improve outcomes.

Purpose: Osteosarcoma may arise as a secondary cancer following leukemias or lymphomas. We intended to increase the knowledge about such rare events. Patients and methods: We searched the Cooperative Osteosarcoma Study Group’s database for individuals who developed their osteosarcoma following a previous hematological malignancy. The presentation and treatment of both malignancies was investigated, and additional neoplasms were noted. Outcomes after osteosarcoma were analyzed and potential prognostic factors were searched for. Results: A total of 33 eligible patients were identified (male: 23, female: 10; median age: 12.9 years at diagnosis of hematological cancer; 20 lymphomas, 13 leukemias). A cancer predisposition syndrome was evident in one patient only. The hematological cancers had been treated by radiotherapy in 28 (1 unknown) and chemotherapy in 26 cases, including bone-marrow transplantation in 9. The secondary bone sarcomas (high-grade central 27, periosteal 2, extra-osseous 2, undifferentiated pleomorphic sarcoma of bone 2) arose after a median lag-time of 9.4 years, when patients were a median of 19.1 years old. Tumors were considered radiation-related in 26 cases (1 unknown). Osteosarcoma-sites were in the extremities (19), trunk (12), or head and neck (2). Metastases at diagnosis affected eight patients. Information on osteosarcoma therapy was available for 31 cases. All of these received chemotherapy. Local therapy involved surgery in 27 patients, with a good response reported for 9/18 eligible patients. Local radiotherapy was given to three patients. The median follow-up was 3.9 (0.3–12.0) years after bone tumor diagnosis. During this period, 21 patients had developed events as defined, and 15 had died, resulting in 5-year event-free and overall survival rates of 40% (standard error: 9%) and 56% (10%), respectively. There were multiple instances of additional neoplasms. Several factors were found to be of prognostic value (p < 0.05) for event-free (osteosarcoma site in the extremities) or overall (achievement of a surgical osteosarcoma-remission, receiving chemotherapy for the hematologic malignancy) survival. Conclusions: We were able to prove radiation therapy for hematological malignancies to be the predominant risk factor for later osteosarcomas. A resulting overrepresentation of axial and a tendency towards additional neoplasms affects prognosis. Still, selected patients may become long-term survivors with appropriate therapies, which is an argument against therapeutic negligence.

Osteosarcoma is a challenging disease requiring multidisciplinary management in expert centers for optimal outcome. There are no current international protocols or guidelines specific for pediatric and adolescent osteosarcoma. The European Standard Clinical Practice (ESCP) project is a collaboration between ERN PaedCan and SIOP Europe’s Clinical Trial Groups to develop approved clinical recommendations reflecting current best practice. This manuscript is a summary of the full ESCP guideline for patients with osteosarcoma. The manuscript provides evidence graded recommendations for diagnosis, staging, management, response evaluation and follow-up. The methodology as defined in the standard operating procedures of the European Society for Medical Oncology (ESMO) was applied. Experts of the Fight OsteoSarcoma Through European Research (FOSTER) consortium contributed. In summary, the ESCP provides guidance on low-grade, but has a focus on high-grade osteosarcoma. In high-grade osteosarcoma the outcomes of most recent trials for clinical subgroups (e.g., metastatic vs. non-metastatic, resectable vs. non-resectable) are discussed, for treatment-naïve as well as for recurrent/refractory disease. An overview of current evidence also highlights the need for further therapeutic development as patients with primary metastatic or recurrent/refractory high-grade osteosarcoma still have a poor prognosis. Intensified collaborative research is identified as a prerequisite to increase survival and to limit long-term toxicities.

Background: To evaluate patient and tumour characteristics, treatment, and their impact on survival in patients with multi-systemic metastases at initial diagnosis of high-grade osteosarcoma. Precedure: Eighty-three consecutive patients who presented with multi-systemic metastases at initial diagnosis of high-grade osteosarcoma were retrospectively reviewed. In cases of curative intent, the Cooperative Osteosarcoma Study Group recommended surgical removal of all detectable metastases in addition to complete resection of the primary tumour and chemotherapy. Results: Eighty-three eligible patients (1.8%) were identified among a total of 4605 individuals with high-grade osteosarcoma. Nine (10.8%) of these achieved complete surgical remission, of whom seven later had recurrences. The median follow-up time was 12 (range, 1–165) months for all patients. Actuarial event-free survival after 1, 2, and 5 years was 9.6 ± 3.2%, 1.4 ± 1.4%, and 1.4 ± 1.4%, and overall survival was 54.0 ± 5.6%, 23.2 ± 4.9%, and 8.7 ± 3.3%. In univariate analyses, elevated alkaline phosphatase before chemotherapy, pleural effusion, distant bones as metastatic sites, and more than one bone metastasis were negative prognostic factors. Among treatment-related factors, the microscopically complete resection of the primary tumour, a good response to first-line chemotherapy, the macroscopically complete resection of all affected tumour sites, and local treatment (surgery ± radiotherapy) of all bone metastases were associated with better outcomes. Tumour progression under first-line treatment significantly correlated with shorter survival times. Conclusion: The outlook for patients with multi-systemic primary metastases from osteosarcoma remains very poor. The utmost importance of surgical resection of all tumour sites was confirmed. For unresectable bone metastases, radiotherapy might be considered. In the patient group studied, standard chemotherapy was often insufficiently effective. In the case of such advanced disease, alternative treatment options are urgently required.

Introduction: Osteosarcoma treatment has benefitted greatly from collaborative research. This paper describes the history and accomplishments of the Cooperative Osteosarcoma Study Group (COSS), mainly dedicated to clinical questions, as well as remaining challenges. Materials and Methods: Narrative review of over four decades of uninterrupted collaboration within the multi-national German–Austrian–Swiss COSS group. Results: Since its very first prospective osteosarcoma trial starting in 1977, COSS has continuously been able to provide high-level evidence on various tumor- and treatment-related questions. This includes both the cohort of patients enrolled into prospective trials as well as those patients excluded from them for various reasons, followed in a prospective registry. Well over one hundred disease-related publications attest to the group’s impact on the field. Despite these accomplishments, challenging problems remain. Discussion: Collaborative research within a multi-national study group resulted in better definitions of important aspects of the most common bone tumor, osteosarcoma, and its treatments. Important challenges continue to persist.

Purpose/Objective(s)Multimodality treatments together with local proton therapy (PT) are commonly used in unresectable primary bone malignancies in order to provide better tumor control rate while maintaining good feasibility. The aim of this study is to provide data on outcome of PT for the challenging cohort of pelvic and lumbar bone tumors.Methods and MaterialsThis retrospective study includes all patients with primary bone malignancy of the pelvis and lumbar spine receiving PT in our institution between May 2013 and December 2019 enrolled in the prospective registries KiProReg and ProReg collecting information on demographics, treatment, tumor characteristics, toxicities, and outcome.ResultsEighty-one patients were enrolled with a median age of 19.7 years (1.3–85.8). The median follow-up time was 27.5 months (1.2–83.2). The majority of patients was male (64.2%), ECOG status of 0–1 (75.2%), underwent only biopsy (50.6%), received chemotherapy (69.1%) and was assigned for definite PT (70.4%). The predominant tumor characteristics were as follows: Ewing’s sarcoma histology (58%), negative nodal involvement (97.5%) and no metastasis at diagnosis (81.5%). Median maximal diameter of tumor was 8 cm (1.4–20). LC, EFS and OS rate were 76.5, 60, and 88.1% at two years and 72.9, 45.7, and 68.9% at three years, respectively. Age over 20 years was a significant negative factor for LC, EFS, and OS. Metastatic disease at initial diagnosis affected OS and ECOG status of 2–4 affected EFS only. Regarding 17 relapsed cases (21%), isolated distant relapse was the most common failure (46.9%) followed by local failure (40.6%). Eleven out of 14 evaluable patients relapsed within high-dose region of radiotherapy. Acute grade 3–4 toxicity was found in 41 patients (50.6%) and all toxicities were manageable. Late grade 3 toxicity was reported in 7 patients (10.4%) without any of grade 4. Most common higher grade acute and late side effects concerned hematologic and musculoskeletal toxicity.ConclusionProton therapy resulted in good oncological outcomes when being part of the multimodality treatment for pelvic and lumbar primary bone malignancies. However, distant metastases and local failures within the high-dose region of radiotherapy are still a common issue. Acute and late toxicities of combined therapy were acceptable.

Genetic association studies suggest a genetic predisposition for cisplatin-induced ototoxicity. Among other candidate genes, thiopurine methyltransferase (TPMT) is considered a critical gene for susceptibility to cisplatin-induced hearing loss in a pharmacogenetic guideline. The PanCareLIFE cross-sectional cohort study evaluated the genetic associations in a large pan-European population and assessed the diagnostic accuracy of the genetic markers. 1,112 pediatric cancer survivors who had provided biomaterial for genotyping were screened for participation in the pharmacogenetic association study. 900 participants qualified for inclusion. Based on the assessment of original audiograms, patients were assigned to three phenotype categories: no, minor, and clinically relevant hearing loss. Fourteen variants in eleven candidate genes (ABCC3, OTOS, TPMT, SLC22A2, NFE2L2, SLC16A5, LRP2, GSTP1, SOD2, WFS1, and ACYP2) were genotyped. The genotype and phenotype data represent a resource for conducting meta-analyses to derive a more precise pooled estimate of the effects of genes on the risk of hearing loss due to platinum treatment.

Osteosarcoma of the foot is a very rare presentation of a rare tumor entity. In a retrospective analysis, we investigated tumor- and treatment-related variables and outcome of patients registered in the Cooperative Osteosarcoma Study Group (COSS) database between January 1980 and April 2016 who suffered from primary high-grade osteosarcoma of the foot. Among the 23 eligible patients, median age was 32 years (range: 6–58 years), 10 were female, and 13 were male. The tarsus was the most commonly affected site (n=16). Three patients had primary metastases. All patients were operated: 5 underwent primary surgery and 18 received surgery following preoperative chemotherapy. In 21 of the 23 patients, complete surgical remission was achieved. In 4 of 17 patients, a poor response to neoadjuvant chemotherapy was observed in the resected primary tumors. Median follow-up was 4.2 years (range: 0.4–18.5). At the last follow-up, 15 of the 23 patients were alive and 8 had died. Five-year overall and event-free survival estimates were 64% (standard error (SE) 12%) and 54% (SE 13%), which is similar to that observed for osteosarcoma in general. Event-free and overall survival correlated with primary metastatic status and completeness of surgery. Our findings show that high-grade osteosarcoma in the foot has a similar outcome as osteosarcoma of other sites.

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.